Substituted-aryl compounds for treatment of disease

ABSTRACT

The invention provides compounds of Formula I: 
                 
 
These compounds may be in the form of pharmaceutical salts or compositions, racemic mixtures, or pure enantiomers thereof. The compounds of Formula I are useful in pharmaceuticals to treat diseases or conditions in which α7 is known to be involved.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. provisional application Ser.No. 60/357,465 and U.S. provisional application Ser. No. 60/357,472 bothof which were filed on Feb. 15, 2002, under 35 USC 119(e)(i), and U.S.provisional application Ser. No. 60/358,083 filed on Feb. 20, 2002,under 35 USC 119(e)(i), which are incorporated herein by reference intheir entirety.

FIELD OF INVENTION

Nicotinic acetylcholine receptors (nAChRs) play a large role in centralnervous system (CNS) activity. Particularly, they are known to beinvolved in cognition, learning, mood, emotion, and neuroprotection.There are several types of nicotinic acetylcholine receptors, and eachone appears to have a different role in regulating CNS function.Nicotine affects all such receptors, and has a variety of activities.Unfortunately, not all of the activities are desirable. In fact, one ofthe least desirable properties of nicotine is its addictive nature andthe low ratio between efficacy and safety. The present invention relatesto molecules that have a greater effect upon the α7 nAChRs as comparedto other closely related members of this large ligand-gated receptorfamily. Thus, the invention provides compounds that are active drugmolecules with fewer side effects.

The invention also concerns the synthesis of and isolation ofintermediates and final compounds. Specifically, the present inventionconcerns the stereospecific synthesis of(3R,5R)-1-azabicyclo[3.2.1]octan-3-amine or salts thereof.

BACKGROUND OF THE INVENTION

Cell surface receptors are, in general, excellent and validated drugtargets. nAChRs comprise a large family of ligand-gated ion channelsthat control neuronal activity and brain function. These receptors havea pentameric structure. In mammals, this gene family is composed of ninealpha and four beta subunits that co-assemble to form multiple subtypesof receptors that have a distinctive pharmacology. Acetylcholine is theendogenous regulator of all of the subtypes, while nicotinenon-selectively activates all nAChRs.

The α7 nAChR is one receptor system that has proved to be a difficulttarget for testing. Native α7 nAChR is not routinely able to be stablyexpressed in most mammalian cell lines (Cooper and Millar, J.Neurochem., 1997, 68(5):2140-51). Another feature that makes functionalassays of α7 nAChR challenging is that the receptor is rapidly (100milliseconds) inactivated. This rapid inactivation greatly limits thefunctional assays that can be used to measure channel activity.

Recently, Eisele et al. has indicated that a chimeric receptor formedbetween the N-terminal ligand binding domain of the α7 nAChR (Eisele etal., Nature, 366(6454), p 479-83, 1993), and the pore forming C-terminaldomain of the 5-HT₃ receptor expressed well in Xenopus oocytes whileretaining nicotinic agonist sensitivity. Eisele et al. used theN-terminus of the avian (chick) form of the α7 nAChR receptor and theC-terminus of the mouse form of the 5-HT₃ gene. However, underphysiological conditions the α7 nAChR is a calcium channel while the5-HT₃R is a sodium and potassium channel. Indeed, Eisele et al. teachesthat the chicken α7 nAChR/mouse 5-HT₃R behaves quite differently thanthe native α7 nAChR with the pore element not conducting calcium butactually being blocked by calcium ions. WO 00/73431 A2 reports on assayconditions under which the 5-HT₃R can be made to conduct calcium. Thisassay may be used to screen for agonist activity at this receptor.

U.S. Pat. No. 5,977,144 discloses compositions for benzylidene- andcinnamylidene-anabaseines and methods for using these compositions fortreating conditions associated with defects or malfunctioning ofnicotinic subtypes brain receptors. These compositions target the α7receptor subtype with little or no activation of the α4β2 or otherreceptor subtypes.

U.S. Pat. No. 5,919,793 discloses heterocyclic derivatives useful inlowering cholesterol levels in blood plasma.

U.S. Pat. No. 5,741,819 discloses arylsulfonylbenzene derivatives andtheir use as factor Xa inhibitors as being useful for the treatment ofarterial and venous thrombotic occlusive disorders, inflammation,cancer, and neurodegenerative diseases.

U.S. Pat. No. 5,723,103 discloses substituted benzamides and radioligandanalogs and methods of using the compounds for the identification of5-HT₃ receptors and the detection and treatment of abnormal conditionsassociated therewith.

U.S. Pat. No. 5,561,149 discloses the use of a mono or bicycliccarbocyclic, or heterocyclic carboxylic, acid ester or amide or animidazolyl carbazol in the manufacture of a medicament suitable for thetreatment of stress-related psychiatric disorders, for increasingvigilance, for the treatment of rhinitis or serotonin-induced disordersand/or coadministration with another active agent to increase thebioavailability thereof, or for nasal administration.

U.S. Pat. No. 5,273,972 discloses novel 2-substituted-3-quinuclidinylarylcarboxamides and arylthiocarboxamides and correspondingarylcarboxylates which have utility as therapeutic agents which exhibitgastric prokinetic, antiemetic, anxiolytic and 5-HT (serotonin)antagonist effects in warm blooded animals.

U.S. Pat. No. 5,237,066 discloses enantiomers of absolute configurationS of amide derivatives of 3-aminoquinuclidine, the process for preparingthem and their use as medicinal products having activity in respect ofgastric movements and antiemetic activity.

U.S. Pat. No. 5,236,931 discloses novel 3-quinuclidinyl benzamides andbenzoates which have utility as therapeutical agents which exhibitanxiolytic, antipsychotic, cognition improvement, antiemetic and gastricprokinetic effects in warm blooded animals.

U.S. Pat. No. 5,206,246 disclosesanxiolytic-R—N-(1-azabicyclo[2.2.2]oct-3-yl)benzamides andthiobenzamides, their N-oxides and pharmaceutically acceptable saltsthereof. A preferred compound isR-(+)-4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxybenzamide.

U.S. Pat. No. 5,106,843 discloses heterocyclic compounds useful as 5-HT₃antagonists.

U.S. Pat. No. 5,084,460 discloses methods of therapeutic treatment withN-(3-quinuclidinyl)-2-hydroxybenzamides and thiobenzamides. Thetherapeutic agents are disclosed as exhibiting anxiolytic antipsychoticand cognitive improving effects in warm blooded animals.

U.S. Pat. No. 5,070,095 discloses novel 1-(azabicyclo[2.2.2]oct-3- or-4-yl)benzamides substituted on the benzene ring with the basicsubstituted aminomethyleneamino group which has been found to be usefulin treating emesis, including emesis due to chemical and radiationanticancer therapy, anxiety, and impaired gastric emptying.

U.S. Pat. No. 5,057,519 discloses 5-HT₃ antagonists as being useful inreducing opiate tolerance.

U.S. Pat. No. 5,039,680 disclose 5-HT₃ antagonists in preventing orreducing dependency on dependency-inducing agents.

U.S. Pat. No. 5,025,022 discloses a method of treating or preventingschizophrenia and/or psychosis usingS—N-(1-azabicyclo[2.2.2]oct-3-yl)benzamides and thiobenzamides, theirN-oxides and pharmaceutically acceptable salts thereof. A preferredcompound isS(−)-4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxybenzamide.

U.S. Pat. No. 5,017,580 discloses memoryenhancing-R—N-(1-azabicyclo[2.2.2]oct-3-yl)benzamides andthiobenzamides, their N-oxides and pharmaceutically acceptable saltsthereof. A preferred compound isR-(+)-4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxybenzamide.

U.S. Pat. No. 4,908,370 disclosesanxiolytic-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamides and thiobenzamidesas having anxiolytic activity, in particular, activity against anxietyinduced by the withdrawal from ingested substances such as narcotics.

U.S. Pat. No. 4,877,794 discloses2-alkoxy-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamide and thiobenzamidecompositions and the use thereof to treat schizophrenia.

U.S. Pat. No. 4,877,780 discloses antiemetic N-substituted benzamideshaving pharmaceutical properties rendering them useful as antiemeticagents with reduced undesirable side effects.

U.S. Pat. No. 4,870,181 discloses a process for the preparation of2-alkoxy-N-(1-azabicyclo[2.2.2])octan-3-yl)aminobenzamide.

U.S. Pat. No. 4,835,162 discloses agonists and antagonists to nicotineas smoking deterrents.

U.S. Pat. No. 4,820,715 discloses anti-emetic quinuclidinyl benzamides.The compounds are particularly useful in the treatment ofchemotherapy-induced emesis in cancer patients. Some of the compoundsare also useful in disorders relating to impaired gastric motility.

U.S. Pat. No. 4,803,199 discloses pharmaceutically useful heterocyclicacid esters and amides or alkylene bridged peperidines as serotonin Mantagonists.

U.S. Pat. No. 4,798,829 discloses 1-azabicyclo[3.2.2]nonane derivativeshaving gastric motility enhancing activity and/or anti-emetic activityand/or 5-HT receptor antagonist activity.

U.S. Pat. No. 4,721,720 discloses a method of treating emesis, anxietyand/or irritable bowel syndrome.

U.S. Pat. No. 4,717,563 discloses2-alkoxy-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamides and thiobenzamides ina method for alleviating emesis caused by non-platinum anticancer drugs.

U.S. Pat. No. 4,657,911 discloses 3-amino quinuclidine derivatives andthe application thereof as accelerators of gastro-intestinal motorfunction and as medicament potentiators.

U.S. Pat. No. 4,605,652 discloses a method of enhancing memory orcorrecting memory deficiency with arylamido (andarylthioamido)-azabicycloalkanes, and the pharmaceutically acceptableacid addition salts, hydrates and alcoholates thereof.

U.S. Pat. No. 4,593,034 discloses2-alkoxy-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamides and thiobenzamideshaving gastrokinetic and anti-emetic activity.

U.S. Pat. No. 4,093,734 discloses amino-benzoic acid amides useful asanxiolytics, anticonvulsives, antiemetics and antiulcerogenics.

U.S. Pat. No. 3,702,324 discloses 3,4,5-trimethoxybenzamides ofsubstituted anilines and of alkylpiperidines which exert a specificeffect on the central nervous system and a somewhat lesser effect onmuscle function, and thus have utility as tranquilizers.

WO 01/76576 A2 discloses a pharmaceutical composition for treatment ofacute, chronic pain and/or neuropathic pain and migraines.

WO 01/60821 A1 discloses novel biarylcarboxamides and their use intherapy, especially in the treatement of prophylaxis of psychotic andintellectual impairment conditions.

WO 01/36417 A1 discloses novel N-azabicyclo-amide derivatives and use intherapy, especially in the treatment of prophylaxis of psychoticdisorders and intellectual impairment disorders.

WO 00/73431 A2 discloses two binding assays to directly measure theaffinity and selectivity of compounds at the α7 nAChR and the 5-HT₃R.The combined use of these functional and binding assays may be used toidentify compounds that are selective agonists of the α7 nAChR.

WO 92/15579 discloses multicyclic tertiary amine polyaromatic squalenesynthase inhibitors and method of treatment for lowering serumcholesterol levels using the compounds.

WO 92/11259 discloses azabicyclic amides or esters of halogenatedbenzoic acids having 5-HT₃ receptor antagonist activity.

FR 2 625 678 discloses N-(quinuclidin-3-yl)-benzamides andthiobenzamides useful as diet-control agents.

In Bioorg. & Med. Chem. Lett. 11 (2001) 319-321, the 5-HT₃ antagonisttropisetron (ICS 205-930) is discussed as a potent and selective α7nicotinic receptor partial agonist.

In Behavioral Brain Res., 113 (2000) 169-181, it is discussed that thebrain α7 nicotinic receptor may be an important therapeutic target forthe treatment of Alzheimer's disease using DMXBA which is known asGTS-21.

SUMMARY OF THE INVENTION

The present invention discloses compounds of the Formula I:

wherein X is O or S;Azabicyclo is

R₀ is H, lower alkyl, lower substituted alkyl, or lower halogenatedalkyl;

R₁ is independently H, alkyl, cycloalkyl, halogenated alkyl, and aryl;

R₂ is F, Cl, Br, I, alkyl, halogenated alkyl, substituted alkyl,cycloalkyl, or aryl, provided that when Azabicyclo is I, R₂ is alkyl,halogenated alkyl, substituted alkyl, cycloalkyl, or aryl, provided thatR₂ is absent when any of k₂, k₃, k₄, k₅, or k₆ is 0;

k₂ is 0 or 1;

k₃ is 0 or 1;

k₄ is 0 or 1;

k₅ is 0, 1, or 2;

k₆ is 0, 1, or 2;

R₃ is H, F, Cl, Br, I, alkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, halogenated alkyl, halogenated alkenyl, halogenatedalkynyl, halogenated cycloalkyl, halogenated heterocycloalkyl, aryl, R₇,R₉, —OR₈, —OR₁₇, —SR₈, —S(O)₂R₈, —S(O)R₈, —OS(O)₂R₈, —NR₈R₈, —NR₁₅R₁₅,—C(O)R₈, —C(O)R₁₆, —C(S)R₈, —C(O)OR₈, —CN, —C(O)NR₈R₈, —C(O)NR₁₅R₁₅,—NR₈C(O)R₈, —S(O)₂NR₈R₈, —NR₈S(O)₂R₈, —NO₂, —N(R₈)C(O)NR₈R₈,—N(H)C(O)N(H)R₈, substituted alkyl, substituted alkenyl, substitutedalkynyl, substituted cycloalkyl, substituted heterocycloalkyl, phenyl,phenyl having 1-4 substituents independently selected from F, Cl, Br, Iand R₂₁, naphthyl, or naphthyl having 1-4 substituents independentlyselected from F, Cl, Br, I, R₂₁;

R₄ is —O—R₅, —S—R₅, —S(O)—R₅, —C(O)—R₅, or alkyl substituted on the ωcarbon with R₅ where said ω carbon is determined by counting the longestcarbon chain of the alkyl moiety with the C-1 carbon being the carbonattached to the phenyl ring of the core molecule and the ω carbon beingthe carbon furthest from said C-1 carbon;

R₅ is aryl, R₇, or R₉;

R₇ is 5-membered heteroaromatic mono-cyclic moieties containing withinthe ring 1-3 heteroatoms independently selected from —O—, ═N—, —N(R₁₄)—,and —S—, and having 0-1 substituent selected from R₁₂ and 0-3substituents independently selected from F, Cl, Br, or I,

or R₇ is a 9-membered fused-ring moiety having a 6-membered ring fusedto a 5-membered ring and having the formula

wherein each A is independently CR₁₈ or N, provided that only up to oneA is N, E¹ and E² are independently selected from CR₁₈, O, S, or NR₁₄,and G is CR₁₈, provided that R₁₈ or R₁₄ of E¹, E², and G can be a bondwhen - - - forms a double bond and further provided that R₁₈ or R₁₄ canbe a bond for bonding R₇ to a moiety to which it is attached;

Each R₈ is independently H, alkyl, halogenated alkyl, substituted alkyl,cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl,heterocycloalkyl, halogenated heterocycloalkyl, substitutedheterocycloalkyl, R₇, R₉, phenyl, or substituted phenyl;

R₉ is 6-membered heteroaromatic mono-cyclic moieties containing withinthe ring 1-3 heteroatoms selected from ═N— and having 0-1 substituentselected from R₁₂ and 0-3 substituent(s) independently selected from F,Cl, Br, or I, or

R₉ is 10-membered heteroaromatic bi-cyclic moieties containing withinone or both rings 1-3 heteroatoms selected from ═N—, includingquinolinyl or isoquinolinyl, each 10-membered fused-ring moiety having0-1 substituent selected from R₁₂ and 0-3 substituent(s) independentlyselected from F, Cl, Br, or I and having a bond for bonding R₉ to amoiety to which it is attached where valency allows;

Each R₁₀ is independently H, alkyl, cycloalkyl, heterocycloalkyl, alkylsubstituted with 1 substituent selected from R₁₃, cycloalkyl substitutedwith 1 substituent selected from R₁₃, heterocycloalkyl substituted with1 substituent selected from R₁₃, halogenated alkyl, halogenatedcycloalkyl, halogenated heterocycloalkyl, phenyl, or phenyl having 1substituent selected from R₂₀ and further having 0-3 substituentsindependently selected from F, Cl, Br, or I;

Each R₁₁ is independently H, alkyl, cycloalkyl, heterocycloalkyl,halogenated alkyl, halogenated cycloalkyl, or halogenatedheterocycloalkyl;

R₁₂ is —OR₁₁, —SR₁₁, alkyl, cycloalkyl, heterocycloalkyl, halogenatedalkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substitutedalkyl, substituted cycloalkyl, substituted heterocycloalkyl, —NR₁₁R₁₁,—C(O)R₁₁, —NO₂, —C(O)NR₁₁R₁₁, —CN, —NR₁₁C(O)R₁₁, —S(O)₂NR₁₁R₁₁, or—NR₁₁S(O)₂R₁₁;

R₁₃ is —OR₁₁, —SR₁₁, —NR₁₁R₁₁, —C(O)R₁₁, —C(O)NR₁₁R₁₁, —CN, —CF₃,—NR₁₁C(O)R₁₁, —S(O)₂NR₁₁R₁₁, —NR₁₁S(O)₂R₁₁, or —NO₂;

R₁₄ is a bond, H, alkyl, halogenated alkyl, substituted alkyl,cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl,heterocycloalkyl, halogenated heterocycloalkyl, substitutedheterocycloalkyl, phenyl, phenyl having 1 substituent selected from R₂₀and further having 0-3 substituents independently selected from F, Cl,Br, or I;

Each R₁₅ is independently alkyl, halogenated alkyl, substituted alkyl,cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl,heterocycloalkyl, halogenated heterocycloalkyl, substitutedheterocycloalkyl, R₇, R₉, phenyl, or substituted phenyl;

Each R₁₆ is independently cycloalkyl, halogenated cycloalkyl,substituted cycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl,substituted heterocycloalkyl, R₇, R₉, phenyl, or substituted phenyl;

Each R₁₇ is independently cycloalkyl, halogenated cycloalkyl,substituted cycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl,or substituted heterocycloalkyl;

Each R₁₈ is independently H, alkyl, cycloalkyl, heterocycloalkyl,halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl,substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl,—OR₁₁, —SR₁₁, —N(R₁₁)₂, —C(O)R₁₁, —NO₂, —C(O)N(R₁₁)₂, —CN, —NR₁₁C(O)R₁₁,—S(O)₂N(R₁₁)₂, or —NR₁₁S(O)₂R₁₁, F, Cl, Br, or I, or a bond;

R₁₉ is H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl,halogenated cycloalkyl, substituted cycloalkyl, phenyl, or phenyl having1 substituent selected from R₂₀ and further having 0-3 substituentsindependently selected from F, Cl, Br, or I;

R₂₀ is alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl,halogenated cycloalkyl, halogenated heterocycloalkyl, —OR₁₁, —SR₁₁,—N(R₁₁)₂, —C(O)R₁₁, —C(O)N(R₁₁)₂, —CN, —NR₁₁C(O)R₁₁, —S(O)₂N(R₁₁)₂,—NR₁₁S(O)₂R₁₁, —NO₂, alkyl substituted with 1-4 substituent(s)independently selected from F, Cl, Br, I, or R₁₃, cycloalkyl substitutedwith 1-4 substituent(s) independently selected from F, Cl, Br, I, orR₁₃, or heterocycloalkyl substituted with 1-4 substituent(s)independently selected from F, Cl, Br, I, or R₁₃;

Each R₂₁ is independently alkyl, halogenated alkyl, substituted alkyl,cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl,heterocycloalkyl, halogenated heterocycloalkyl, substitutedheterocycloalkyl, R₇, R₉, phenyl, or phenyl having 1 substituentselected from R₂₀ and further having 0-3 substituents independentlyselected from F, Cl, Br, or I;

or pharmaceutical composition, pharmaceutically acceptable salt, racemicmixture, or pure enantiomer thereof.

The compounds of Formula I are used to treat a disease or condition,wherein the diseases, disorders, and/or condition is any one or more orcombination of the following: cognitive and attention deficit symptomsof Alzheimer's, neurodegeneration associated with diseases such asAlzheimer's disease, pre-senile dementia (mild cognitive impairment),senile dementia, schizophrenia, psychosis, attention deficit disorder,attention deficit hyperactivity disorder, depression, anxiety, generalanxiety disorder, post traumatic stress disorder, mood and affectivedisorders, amyotrophic lateral sclerosis, borderline personalitydisorder, traumatic brain injury, behavioral and cognitive problems ingeneral and associated with brain tumors, AIDS dementia complex,dementia associated with Down's syndrome, dementia associated with LewyBodies, Huntington's disease, Parkinson's disease, tardive dyskinesia,Pick's disease, dysregulation of food intake including bulemia andanorexia nervosa, withdrawal symptoms associated with smoking cessationand dependant drug cessation, Gilles de la Tourette's Syndrome,age-related macular degeneration, glaucoma, neurodegeneration associatedwith glaucoma, or symptoms associated with pain.

Embodiments of the invention may include one or more or combination ofthe following.

The compound of Formula I, wherein X is O. The compound of Formula I,where X is S.

The compound of Formula I, where Azabicyclo is any one or more of I, II,III, IV, V, or VI.

Another group of compounds of Formula I include compounds where R₁ isany one of the following: H, alkyl, cycloalkyl, halogenated alkyl, andaryl. Another group of compounds of Formula I include compounds where R₁is H, lower alkyl, or lower cycloalkyl.

Another group of compounds of Formula I include compounds whereAzabicyclo is II, V, or VI and where each k₂, k₅, and k₆ isindependently 0 or 1. Another group of compounds of Formula I includecompounds where R₂ is lower alkyl, lower halogenated alkyl, lowersubstituted alkyl, or is absent provided that k₂, k₃, k₄, k₅, or k₆ is0. When k₂, k₃, k₄, k₅, or k₆ is 0, R₂ is “absent.” Another group ofcompounds of Formula I include compounds where R₁ is H or lower alkyl,and wherein R₂ is lower alkyl or is absent.

Another group of compounds of Formula I include compounds whereAzabicyclo is I and where R₂ is lower alkyl, lower halogenated alkyl, orlower substituted alkyl, or where Azabicyclo is III or IV and where R₂is absent, lower alkyl, or lower substituted alkyl.

Another group of compounds within the present invention includescompounds where X is O. The present invention also includes compoundswhere R₀ is H. Other compounds within the scope of the present inventionare where R₀ is methyl. The present invention also includes compoundswhere R₁ is H. Other compounds within the scope of the present inventionare where R₁ is alkyl, cycloalkyl, halogenated alkyl, or aryl. Thepresent invention also includes compounds where R₂ is absent, providedthat R₂ is present when Azabicyclo is I. Other compounds within thescope of the present invention are where R₂ is alkyl, halogenated alkyl,substituted alkyl, cycloalkyl, or aryl.

Another group of compounds within the present invention includescompounds where R₃ is any one or more of the following: H, F, Cl, Br, I,alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, halogenatedalkyl, halogenated alkenyl, halogenated alkynyl, halogenated cycloalkyl,halogenated heterocycloalkyl, aryl, R₇, R₉, —OR₈, —OR₁₇, —SR₈, —S(O)₂R₈,—S(O)R₈, —OS(O)₂R₈, —NR₈R₈, —NR₁₅R₁₅, —C(O)R₈, —C(O)R₁₆, —C(S)R₈,—C(O)OR₈, —CN, —C(O)NR₈R₈, —C(O)NR₁₅R₁₅, —NR₈C(O)R₈, —S(O)₂NR₈R₈,—NR₈S(O)₂R₈, —NO₂, —N(R₈)C(O)NR₈R₈, —N(H)C(O)N(H)R₈, substituted alkyl,substituted alkenyl, substituted alkynyl, substituted cycloalkyl,substituted heterocycloalkyl, phenyl, phenyl having 1-4 substituentsindependently selected from F, Cl, Br, I and R₂₁, naphthyl, or naphthylhaving 1-4 substituents independently selected from F, Cl, Br, I, R₂₁.Another group of compounds within the present invention includescompounds where R₃ is H. Another group of compounds within the presentinvention includes compounds where R₃ is any one or more of thefollowing: H, F, Cl, Br, I, lower alkyl, lower halogenated alkyl, —OR₈,—OR₁₇, —N(R₈)₂, —NR₁₅R₁₅, —C(O)N(R₈)₂, —NR₈C(O)R₈.

Another group of compounds within the present invention includescompounds where each R₈ is independently any one or more of thefollowing: H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl,halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl,halogenated heterocycloalkyl, substituted heterocycloalkyl, R₇, R₉,phenyl, or substituted phenyl.

Another group of compounds within the present invention includescompounds where each R₁₀ is independently any one or more of thefollowing: H, alkyl, cycloalkyl, heterocycloalkyl, alkyl substitutedwith 1 substituent selected from R₁₃, cycloalkyl substituted with 1substituent selected from R₁₃, heterocycloalkyl substituted with 1substituent selected from R₁₃, halogenated alkyl, halogenatedcycloalkyl, halogenated heterocycloalkyl, phenyl, or phenyl having 1substituent selected from R₂₀ and further having 0-3 substituentsindependently selected from F, Cl, Br, or I.

Another group of compounds within the present invention includescompounds where R₁₄ is any one or more of the following: a bond, H,alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenatedcycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenatedheterocycloalkyl, substituted heterocycloalkyl, phenyl, phenyl having 1substituent selected from R₂₀ and further having 0-3 substituentsindependently selected from F, Cl, Br, or I.

Another group of compounds within the present invention includescompounds where each R₁₅ is independently any one or more of thefollowing: alkyl, halogenated alkyl, substituted alkyl, cycloalkyl,halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl,halogenated heterocycloalkyl, substituted heterocycloalkyl, R₇, R₉,phenyl, or substituted phenyl;

Another group of compounds within the present invention includescompounds where each R₁₆ is independently any one or more of thefollowing: cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl,heterocycloalkyl, halogenated heterocycloalkyl, substitutedheterocycloalkyl, R₇, R₉, phenyl, or substituted phenyl.

Another group of compounds within the present invention includescompounds where R₁₇ is any one or more of the following: cycloalkyl,halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl,halogenated heterocycloalkyl, or substituted heterocycloalkyl.

Another group of compounds within the present invention includescompounds where each R₁₈ is independently any one or more of thefollowing: H, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl,halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl,substituted cycloalkyl, substituted heterocycloalkyl, —OR₁₁, —SR₁₁,—N(R₁₁)₂, —C(O)R₁₁, —NO₂, —C(O)N(R₁₁)₂, —CN, —NR₁₁C(O)R₁₁,—S(O)₂N(R₁₁)₂, or —NR₁₁S(O)₂R₁₁, F, Cl, Br, or I, or a bond.

Another group of compounds within the present invention includescompounds where R₄ is any one or more of the following: —O—R₅, —S—R₅,—S(O)—R₅, —C(O)—R₅. Another group of compounds within the presentinvention includes compounds where R₅ is aryl, R₇, or R₉.

The ω carbon is determined by counting the longest carbon chain of thealkyl-type moiety with the C-1 carbon being the carbon attached to thephenyl ring of the core molecule and the ω carbon being the carbonfurthest, e.g., separated by the greatest number of carbon atoms in thechain, from said C-1 carbon.

The core molecule is the Azabicyclo-(carboxamide-type moiety)-phenyl:

Therefore, when determining the ω carbon, the C-1 carbon will be thecarbon attached to the phenyl ring of the core molecule and the ω carbonwill be the carbon furthest from said C-1 carbon.

Another group of compounds within the present invention includescompounds where R₄ is alkyl substituted on the ω carbon with R₅ wheresaid ω carbon is determined by counting the longest carbon chain of thealkyl moiety with the C-1 carbon being the carbon attached to the phenylring of the core molecule and the ω carbon being the carbon furthestfrom said C-1 carbon.

Another group of compounds within the present invention includescompounds where R₄ is attached to the phenyl ring of the core moleculeat C4 and where R₃ is attached to the phenyl ring of the core moleculeat a carbon adjacent to the C-4 carbon, including:

One of ordinary skill in the art will recognize that where alkyl,halogenated alkyl, substituted alkyl, alkenyl, halogenated alkenyl,substituted alkenyl, alkynyl, halogenated alkynyl, or substitutedalkynyl is allowed, the following, respectively, are also allowed: loweralkyl, lower halogenated alkyl, lower substituted alkyl, lower alkenyl,lower halogenated alkenyl, lower substituted alkenyl, lower alkynyl,lower halogenated alkynyl, or lower substituted alkynyl.

A further embodiment of the present invention includes the compounds ofthe present invention, pharmaceutical compositions containing the activecompounds as the free base or as a pharmaceutically acceptable salt anda pharmaceutically acceptable carrier, and methods to treat theidentified diseases.

In another aspect, the invention includes treating a mammal sufferingfrom schizophrenia or psychosis by administering compounds of Formula Iin conjunction with antipsychotic drugs (also called anti-psychoticagents). The compounds of the present invention and the antipsychoticdrugs can be administered simultaneously or at separate intervals. Whenadministered simultaneously, the compounds of the present invention andthe antipsychotic drugs can be incorporated into a single pharmaceuticalcomposition. Alternatively, two separate compositions, i.e., onecontaining compounds of the present invention and at least one othercontaining antipsychotic drugs, can be administered simultaneously.

A further embodiment of the present invention provides a methodcomprising administering a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositioncontains said compound to the mammal.

The present invention also includes pharmaceutical composition(s)comprising a compound of Formula I or a pharmaceutically acceptable saltthereof and a pharmaceutically acceptable excipient, and optionallyanti-psychotic agent(s). The pharmaceutical composition(s) is (are)administered rectally, topically, orally, sublingually, or parenterallyfor a therapeutically effective interval. The pharmaceutical compositioncontaining the compound of Formula I is administered to deliver thecompound in an amount of from about 0.001 to about 100 mg/kg of bodyweight of said mammal per day. The pharmaceutical composition is alsoadministered to deliver the compound in an amount of from about 0.1 toabout 50 mg/kg of body weight of said mammal per day.

The present invention also includes a method to treat using a compoundaccording to Formula I or pharmaceutically acceptable salt thereof, oruse of a compound according to Formula I or pharmaceutically acceptablesalt thereof to prepare a medicament for treating, a disease orcondition, wherein the mammal would receive symptomatic relief from theadministration of a therapeutically effective amount of α7 nicotinicacetylcholine receptor agonist.

The present invention also includes a method to treat using a compoundaccording to Formula I or pharmaceutically acceptable salt thereof, oruse of a compound according to Formula I or pharmaceutically acceptablesalt thereof to prepare a medicament for treating, a disease orcondition, wherein the mammal would receive symptomatic relief from theadministration of a therapeutically effective amount of α7 nicotinicacetylcholine receptor agonist, wherein the disease, or condition is anyone or more or combination of the following: cognitive and attentiondeficit symptoms of Alzheimer's, neurodegeneration associated withdiseases such as Alzheimer's disease, pre-senile dementia (mildcognitive impairment), senile dementia, schizophrenia, psychosis,attention deficit disorder, attention deficit hyperactivity disorder,depression, anxiety, general anxiety disorder, post traumatic stressdisorder, mood and affective disorders, amyotrophic lateral sclerosis,borderline personality disorder, traumatic brain injury, behavioral andcognitive problems in general and associated with brain tumors, AIDSdementia complex, dementia associated with Down's syndrome, dementiaassociated with Lewy Bodies, Huntington's disease, Parkinson's disease,tardive dyskinesia, Pick's disease, dysregulation of food intakeincluding bulemia and anorexia nervosa, withdrawal symptoms associatedwith smoking cessation and dependant drug cessation, Gilles de laTourette's Syndrome, age-related macular degeneration, glaucoma,neurodegeneration associated with glaucoma, or symptoms associated withpain.

The compounds of Formula I (Azabicyclo is I) have asymmetric center(s)on the quinuclidine ring. The compounds of the present invention includequinuclidines with the 3R configuration or 3S configuration and alsoincludes racemic mixtures, the separate stereoisomers, and compositionsof varying degrees of stereochemical purity. For example, and not bylimitation, compounds of Formula I include compounds withstereospecificity including:

The compounds of Formula I (Azabicyclo is II) have asymmetric center(s)on the [2.2.1] azabicyclic ring at C3 and C4. The scope of thisinvention includes racemic mixtures of varying degrees of stereochemicalpurities, the separate stereoisomers, and compositions of varyingdegrees of stereochemical purities of Formula I being endo-4S, endo-4R,exo-4S, exo-4R:

The endo isomer is the isomer where the non-hydrogen substituent at C3of the [2.2.1] azabicyclic compound is projected toward the larger ofthe two remaining bridges. The exo isomer is the isomer where thenon-hydrogen substituent at C3 of the [2.2.1] azabicyclic compound isprojected toward the smaller of the two remaining bridges. Thus, therecan be four separate isomers: exo-4(R), exo-4(S), endo-4(R), andendo-4(S).

The compounds of Formula I (Azabicyclo III) have asymmetric center(s) onthe [2.2.1] azabicyclic ring at C1, C4 and C5. The scope of thisinvention includes racemic mixtures of varying degrees of stereochemicalpurities, the separate stereoisomers, and compositions of varyingdegrees of stereochemical purities of Formula I being (1R,4R,5S),(1R,4R,5R), (1S,4S,5R), (1S,4S,5S):

The endo isomer is the isomer where the non-hydrogen substituent at C5of the [2.2.1] azabicyclic compound is projected toward the larger ofthe two remaining bridges. The exo isomer is the isomer where thenon-hydrogen substituent at C5 of the [2.2.1] azabicyclic compound isprojected toward the smaller of the two remaining bridges. Thus, therecan be four separate isomers: exo-(1R,4R,5S), exo-(1S,4S,5R),endo-(1S,4S,5S), endo-(1R,4R,5R).

The compounds of Formula I (Azabicyclo IV) have asymmetric center(s) onthe [2.2.1] azabicyclic ring at C1, C4 and C6. The scope of thisinvention includes racemic mixtures of varying degrees of stereochemicalpurities, the separate stereoisomers, and compositions of varyingdegrees of stereochemical purities of Formula I being exo-(1S,4R,6S),exo-(1R,4S,6R), endo-(1S,4R,6R), and endo-(1R,4S,6S):

The endo isomer is the isomer where the non-hydrogen substituent at C6of the [2.2.1] azabicyclic compound is projected toward the larger ofthe two remaining bridges. The exo isomer is the isomer where thenon-hydrogen substituent at C6 of the [2.2.1] azabicyclic compound isprojected toward the smaller of the two remaining bridges. Thus, therecan be four separate isomers: exo-(1S,4R,6S), exo-(1R,4S,6R),endo-(1S,4R,6R), and endo-(1R,4S,6S).

The compounds of Formula I (Azabicyclo is V) have asymmetric center(s)on the [3.2.1] azabicyclic ring at C3 and C5. The scope of thisinvention includes racemic mixtures of varying degrees of stereochemicalpurities, the separate stereoisomers, and compositions of varyingdegrees of stereochemical purities of Formula I being endo-3S, 5R,endo-3R, 5S, exo-3R, 5R, exo-3S, 5S:

The compounds of Formula I (Azabicyclo is VI) have asymmetric centers onthe [3.2.2] azabicyclic ring with one center being at C3 when R₂ isabsent. The scope of this invention includes racemic mixtures of varyingdegrees of stereochemical purities, the separate stereoisomers, andcompositions of varying degrees of stereochemical purities of Formula Ibeing 3(S) and 3(R):

The compounds of the present invention having the specifiedstereochemistry have different levels of activity and that for a givenset of values for the variable substitutuents one isomer may bepreferred over the other isomers. Although it is desirable that thestereochemical purity be as high as possible, absolute purity is notrequired. This invention involves racemic mixtures and compositions ofvarying degrees of stereochemical purities when the Azabicyclo issubstituted with only the amide/thioamide or is substituted withsubstituents in addition to the amide/thioamide, e.g., R₂ is alkyl. Whenracemic mixtures and compositions are referenced, it is meant racemicmixtures and compositions of varying degrees of stereochemical purities.It is preferred to carry out stereoselective syntheses and/or to subjectthe reaction product to appropriate purification steps so as to producesubstantially enantiomerically pure materials. Suitable stereoselectivesynthetic procedures for producing enantiomerically pure materials arewell known in the art, as are procedures for purifying racemic mixturesinto enantiomerically pure fractions.

Stereoselective syntheses and/or subjecting the reaction product toappropriate purification steps produces substantially enantiomericallypure materials. Suitable stereoselective synthetic procedures forproducing enantiomerically pure materials are well known in the art, asare procedures for purifying racemic mixtures into enantiomerically purefractions.

Another embodiment of the compounds of Formula I includes any one ormore or combination of the following configurations for compounds:

where (i) the compound is a mixture of diastereomers,

(ii) the compound has the R absolute stereochemistry at C-3 as discussedherein and stereochemistry is unspecified at C-6, or

(iii) the compound has the S absolute stereochemistry at C-3 asdiscussed herein and stereochemistry is unspecified at C-6.

Another embodiment of compounds of Formula I includes any one or more orcombination of the following configurations for compounds:

where (i) R₂ is absent;

(ii) R₂ is alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, oraryl;

(iii) R₂ is alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, oraryl; or

(iv) the 2.2.1 moiety has the exo-4(S) absolute stereochemistry and R₂has any definition as discussed herein.

Another embodiment of compounds of Formula I includes any one or more orcombination of the following configurations for compounds:

where (i) R₂ is absent;

(ii) R₂ is F, Cl, Br, I, alkyl, halogenated alkyl, substituted alkyl,cycloalkyl, or aryl; or

(iii) R₂ is alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, oraryl.

Another embodiment of compounds of Formula I includes any one or more orcombination of the following configurations for compounds:

where (i) R₂ is absent;

(ii) R₂ is F, Cl, Br, I, alkyl, halogenated alkyl, substituted alkyl,cycloalkyl, or aryl; or

(iii) R₂ is alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, oraryl.

Another embodiment of compounds of Formula I includes any one or more orcombination of the following configurations for compounds:

where (i) R₂ is absent;

(ii) R₂ has any definition as discussed herein and where the Azabicyclohas the absolute stereochemistry of 3R, 5R;

(iii) k₅ is 2, where R_(2-a) is alkyl, halogenated alkyl, substitutedalkyl, cycloalkyl, or aryl, and where R_(2-b) is F, Cl, Br, I, alkyl,halogenated alkyl, substituted alkyl, cycloalkyl, or aryl;

(iv) k₅ is 1, where R₂ is alkyl, halogenated alkyl, substituted alkyl,cycloalkyl, or aryl; or

(v) k₅ is 1, where R₂ is F, Cl, Br, I, alkyl, halogenated alkyl,substituted alkyl, cycloalkyl, or aryl.

Another embodiment of compounds of Formula I includes any one or more orcombination of the following configurations for compounds:

where (i) R₂ is absent;

(ii) k₆ is 2, where each R_(2-a) is alkyl, halogenated alkyl,substituted alkyl, cycloalkyl, or aryl and where each R_(2-b) is F, Cl,Br, I, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, or aryl;

(iii) k₆ is 1, where R₂ is alkyl, halogenated alkyl, substituted alkyl,cycloalkyl, or aryl; or

(iv) k₆ is 1, where R₂ is F, Cl, Br, I, alkyl, halogenated alkyl,substituted alkyl, cycloalkyl, or aryl.

Another aspect of the present invention includes, by representation butnot limitation, any compound named or exemplified as a single compoundor any combination thereof and pharmaceutically acceptable salt thereof,discussed herein.

The invention also concerns the synthesis of and isolation ofstereospecific intermediates and final compounds. Specifically, thepresent invention concerns the stereoselective synthesis of(3R,5R)-1-azabicyclo[3.2.1]octan-3-amine, or salts thereof. Althoughthere are known procedures for making 1-azabicyclo[3.2.1]octan-3-amine,separation of the different stereoismers as described herein occurswithout using a chiral HPLC separation procedure. The procedure withinthis invention results in an efficient selective synthesis of(3R,5R)-1-azabicyclo[3.2.1]octan-3-amine.

Another aspect of the present invention includes a method for making(3R,5R)-1-azabicyclo[3.2.1]octan-3-amine or salt thereof. One processfor producing (3R,5R)-1-azabicyclo[3.2.1]octan-3-amine or a saltthereof, from (3R)-methyl 1-[(S)-1-phenylethyl]pyrrolidine-3-acetate,comprises: the process of producing(5R)-3-oxo-1-[(1S)-1-phenylethyl]-1-azoniabicyclo[3.2.1]octane chloridefrom (3R)-methyl 1-[(S)-1-phenylethyl]pyrrolidine-3-acetate;

the process of producing (5R)-1-azabicyclo[3.2.1]octan-3-one or a saltthereof from(5R)-3-oxo-1-[(1S)-1-phenylethyl]-1-azoniabicyclo[3.2.1]octane chloride;

and the process of producing (3R,5R)-1-azabicyclo[3.2.1]octan-3-amine ora salt thereof from (5R)-1-azabicyclo[3.2.1]octan-3-one or a saltthereof.

Another process comprises: the process of producing (3R)-methyl1-[(S)-1-phenylethyl]pyrrolidine-3-acetate from(3R)-1-[(S)-1-phenethyl]-3-(cyanomethyl)pyrrolidine;

the process of producing(5R)-3-oxo-1-[(1S)-1-phenylethyl]-1-azoniabicyclo[3.2.1]octane chloridefrom (3R)-methyl 1-[(S)-1-phenylethyl]pyrrolidine-3-acetate;

the process of producing (5R)-1-azabicyclo[3.2.1]octan-3-one or a saltthereof from(5R)-3-oxo-1-[(1S)-1-phenylethyl]-1-azoniabicyclo[3.2.1]octane chloride;

and the process of producing (3R,5R)-1-azabicyclo[3.2.1]octan-3-amine ora salt thereof from (5R)-1-azabicyclo[3.2.1]octan-3-one or a saltthereof.

Another process comprises: the process of producing(3S)-1-[(S)-1-phenethyl]-5-oxo-3-pyrrolidine-carboxylic acid from(S)-(−)-α-methyl benzylamine;

the process of isolating(3S)-1-[(S)-1-phenethyl]-5-oxo-3-pyrrolidine-carboxylic acid from aracemic mixture using a precipitating solvent without causing theprecipitation of other isomers, where the solvent can include a primaryalcohol, including but not limited to methanol;

the process of producing(3S)-1-[(S)-1-phenethyl]-3-(hydroxymethyl)pyrrolidine from(3S)-1-[(S)-1-phenethyl]-5-oxo-3-pyrrolidine-carboxylic acid;

the process of producing(3S)-1-[(S)-1-phenethyl]-3-(chloromethyl)pyrrolidine from(3S)-1-[(S)-1-phenethyl]-3-(hydroxymethyl)pyrrolidine;

the process of producing(3R)-1-[(S)-1-phenethyl]-3-(cyanomethyl)pyrrolidine from(3S)-1-[(S)-1-phenethyl]-3-(chloromethyl)pyrrolidine;

the process of producing (3R)-methyl1-[(S)-1-phenylethyl]pyrrolidine-3-acetate from(3R)-1-[(S)-1-phenethyl]-3-(cyanomethyl)pyrrolidine;

the process of producing(5R)-3-oxo-1-[(1S)-1-phenylethyl]-1-azoniabicyclo[3.2.1]octane chloridefrom (3R)-methyl 1-[(S)-1-phenylethyl]pyrrolidine-3-acetate;

the process of producing (5R)-1-azabicyclo[3.2.1]octan-3-one or saltthereof from(5R)-3-oxo-1-[(1S)-1-phenylethyl]-1-azoniabicyclo[3.2.1]octane chloride;

and the process of producing (3R,5R)-1-azabicyclo[3.2.1]octan-3-amine orsalt thereof from (5R)-1-azabicyclo[3.2.1]octan-3-one or salt thereof.

Another process comprises: the process of producing(3S)-1-[(S)-1-phenethyl]-5-oxo-3-pyrrolidine-carboxylic acid from(S)-(−)-α-methyl benzylamine;

the process of producing(3S)-1-[(S)-1-phenethyl]-3-(hydroxymethyl)pyrrolidine from(3S)-1-[(S)-1-phenethyl]-5-oxo-3-pyrrolidine-carboxylic acid;

the process of producing(3S)-1-[(S)-1-phenethyl]-3-(chloromethyl)pyrrolidine from(3S)-1-[(S)-1-phenethyl]-3-(hydroxymethyl)pyrrolidine;

the process of producing(3R)-1-[(S)-1-phenethyl]-3-(cyanomethyl)pyrrolidine from(3S)-1-[(S)-1-phenethyl]-3-(chloromethyl)pyrrolidine;

the process of producing (3R)-methyl1-[(S)-1-phenylethyl]pyrrolidine-3-acetate from(3R)-1-[(S)-1-phenethyl]-3-(cyanomethyl)pyrrolidine;

the process of producing(5R)-3-oxo-1-[(1S)-1-phenylethyl]-1-azoniabicyclo[3.2.1]octane chloridefrom (3R)-methyl 1-[(S)-1-phenylethyl]pyrrolidine-3-acetate;

the process of producing (5R)-1-azabicyclo[3.2.1]octan-3-one or saltthereof from(5R)-3-oxo-1-[(1S)-1-phenylethyl]-1-azoniabicyclo[3.2.1]octane chloride;

and the process of producing (3R,5R)-1-azabicyclo[3.2.1]octan-3-amine orsalt thereof from (5R)-1-azabicyclo[3.2.1]octan-3-one or salt thereof.

Further aspects and embodiments of the invention may become apparent tothose skilled in the art from a review of the following detaileddescription, taken in conjunction with the examples and the appendedclaims. While the invention is susceptible of embodiments in variousforms, described hereafter are specific embodiments of the inventionwith the understanding that the present disclosure is intended asillustrative, and is not intended to limit the invention to the specificembodiments described herein.

DETAILED DESCRIPTION OF THE INVENTION

Surprisingly, we have found that compounds of Formula I:

wherein X is O or S;Azabicyclo is

R₀ is H, lower alkyl, lower substituted alkyl, or lower halogenatedalkyl;

R₁ is independently H, alkyl, cycloalkyl, halogenated alkyl, and aryl;

R₂ is F, Cl, Br, I, alkyl, halogenated alkyl, substituted alkyl,cycloalkyl, or aryl, provided that when Azabicyclo is I, R₂ is alkyl,halogenated alkyl, substituted alkyl, cycloalkyl, or aryl, provided thatR₂ is absent when any of k₂, k₃, k₄, k₅, or k₆ is 0;

k₂ is 0 or 1;

k₃ is 0 or 1;

k₄ is 0 or 1;

k₅ is 0, 1, or 2;

k₆ is 0, 1, or 2;

R₃ is H, F, Cl, Br, I, alkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, halogenated alkyl, halogenated alkenyl, halogenatedalkynyl, halogenated cycloalkyl, halogenated heterocycloalkyl, aryl, R₇,R₉, —OR₈, —OR₁₇, —SR₈, —S(O)₂R₈, —S(O)R₈, —OS(O)₂R₈, —NR₈R₈, —NR₁₅R₁₅,—C(O)R₈, —C(O)R₁₆, —C(S)R₈, —C(O)OR₈, —CN, —C(O)NR₈R₈, —C(O)NR₁₅R₁₅,—NR₈C(O)R₈, —S(O)₂NR₈R₈, —NR₈S(O)₂R₈, —NO₂, —N(R₈)C(O)NR₈R₈,—N(H)C(O)N(H)R₈, substituted alkyl, substituted alkenyl, substitutedalkynyl, substituted cycloalkyl, substituted heterocycloalkyl, phenyl,phenyl having 1-4 substituents independently selected from F, Cl, Br, Iand R₂₁, naphthyl, or naphthyl having 1-4 substituents independentlyselected from F, Cl, Br, I, R₂₁;

R₄ is —O—R₅, —S—R₅, —S(O)—R₅, —C(O)—R₅, or alkyl substituted on the ωCARBON with R₅ where said ω carbon is determined by counting the longestcarbon chain of the alkyl moiety with the C-1 carbon being the carbonattached to the phenyl ring of the core molecule and the co carbon beingthe carbon furthest from said C-1 carbon;

R₅ is aryl, R₇, or R₉;

R₇ is 5-membered heteroaromatic mono-cyclic moieties containing withinthe ring 1-3 heteroatoms independently selected from —O—, ═N—, —N(R₁₄)—,and —S—, and having 0-1 substituent selected from R₁₂ and 0-3substituents independently selected from F, Cl, Br, or I,

or R₇ is a 9-membered fused-ring moiety having a 6-membered ring fusedto a 5-membered ring and having the formula:

wherein each A is independently CR₁₈ or N, provided that only up to oneA is N, E¹ and E² are independently selected from CR₁₈, O, S, or NR₁₄,and G is CR₁₈, provided that R₁₈ or R₁₄ of E¹, E², and G can be a bondwhen - - - forms a double bond and further provided that R₁₈ or R₁₄ canbe a bond for bonding R₇ to a moiety to which it is attached;

Each R₈ is independently H, alkyl, halogenated alkyl, substituted alkyl,cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl,heterocycloalkyl, halogenated heterocycloalkyl, substitutedheterocycloalkyl, R₇, R₉, phenyl, or substituted phenyl;

R₉ is 6-membered heteroaromatic mono-cyclic moieties containing withinthe ring 1-3 heteroatoms selected from ═N— and having 0-1 substituentselected from R₁₂ and 0-3 substituent(s) independently selected from F,Cl, Br, or I, or

R₉ is 10-membered heteroaromatic bi-cyclic moieties containing withinone or both rings 1-3 heteroatoms selected from ═N—, includingquinolinyl or isoquinolinyl, each 10-membered fused-ring moiety having0-1 substituent selected from R₁₂ and 0-3 substituent(s) independentlyselected from F, Cl, Br, or I and having a bond for bonding R₉ to amoiety to which it is attached where valency allows;

Each R₁₀ is independently H, alkyl, cycloalkyl, heterocycloalkyl, alkylsubstituted with 1 substituent selected from R₁₃, cycloalkyl substitutedwith 1 substituent selected from R₁₃, heterocycloalkyl substituted with1 substituent selected from R₁₃, halogenated alkyl, halogenatedcycloalkyl, halogenated heterocycloalkyl, phenyl, or phenyl having 1substituent selected from R₂₀ and further having 0-3 substituentsindependently selected from F, Cl, Br, or I;

Each R₁₁ is independently H, alkyl, cycloalkyl, heterocycloalkyl,halogenated alkyl, halogenated cycloalkyl, or halogenatedheterocycloalkyl;

R₁₂ is —OR₁₁, —SR₁₁, alkyl, cycloalkyl, heterocycloalkyl, halogenatedalkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substitutedalkyl, substituted cycloalkyl, substituted heterocycloalkyl, —NR₁₁R₁₁,—C(O)R₁₁, —NO₂, —C(O)NR₁₁R₁₁, —CN, —NR₁₁C(O)R₁₁, —S(O)₂NR₁₁R₁₁, or—NR₁₁S(O)₂R₁;

R₁₃ is —OR₁₁, —SR₁₁, —NR₁₁R₁₁, —C(O)R₁₁, —C(O)NR₁₁R₁₁, —CN, —CF₃,—NR₁₁C(O)R₁₁, —S(O)₂NR₁₁R₁₁, —NR₁₁S(O)₂R₁₁, or —NO₂;

R₁₄ is a bond, H, alkyl, halogenated alkyl, substituted alkyl,cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl,heterocycloalkyl, halogenated heterocycloalkyl, substitutedheterocycloalkyl, phenyl, phenyl having 1 substituent selected from R₂₀and further having 0-3 substituents independently selected from F, Cl,Br, or I;

Each R₁₅ is independently alkyl, halogenated alkyl, substituted alkyl,cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl,heterocycloalkyl, halogenated heterocycloalkyl, substitutedheterocycloalkyl, R₇, R₉, phenyl, or substituted phenyl;

Each R₁₆ is independently cycloalkyl, halogenated cycloalkyl,substituted cycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl,substituted heterocycloalkyl, R₇, R₉, phenyl, or substituted phenyl;

Each R₁₇ is independently cycloalkyl, halogenated cycloalkyl,substituted cycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl,or substituted heterocycloalkyl;

Each R₁₈ is independently H, alkyl, cycloalkyl, heterocycloalkyl,halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl,substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl,—OR₁₁, —SR₁₁, —N(R₁₁)₂, —C(O)R₁₁, —NO₂, —C(O)N(R₁₁)₂, —CN, —NR₁₁C(O)R₁₁,—S(O)₂N(R₁₁)₂, or —NR₁₁S(O)₂R₁₁, F, Cl, Br, or I, or a bond;

R₁₉ is H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl,halogenated cycloalkyl, substituted cycloalkyl, phenyl, or phenyl having1 substituent selected from R₂₀ and further having 0-3 substituentsindependently selected from F, Cl, Br, or I;

R₂₀ is alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl,halogenated cycloalkyl, halogenated heterocycloalkyl, —OR₁₁, —SR₁₁,—N(R₁₁)₂, —C(O)R₁₁, —C(O)N(R₁₁)₂, —CN, —NR₁₁C(O)R₁₁, —S(O)₂N(R₁₁)₂,—NR₁₁S(O)₂R₁₁ , —NO₂, alkyl substituted with 1-4 substituent(s)independently selected from F, Cl, Br, I, or R₁₃, cycloalkyl substitutedwith 1-4 substituent(s) independently selected from F, Cl, Br, I, orR₁₃, or heterocycloalkyl substituted with 1-4 substituent(s)independently selected from F, Cl, Br, I, or R₁₃;

Each R₂₁ is independently alkyl, halogenated alkyl, substituted alkyl,cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl,heterocycloalkyl, halogenated heterocycloalkyl, substitutedheterocycloalkyl, R₇, R₉, phenyl, or phenyl having 1 substituentselected from R₂₀ and further having 0-3 substituents independentlyselected from F, Cl, Br, or I;

Aryl is phenyl, substituted phenyl, naphthyl, or substituted naphthyl;

Substituted phenyl is a phenyl either having 1-4 substituentsindependently selected from F, Cl, Br, or I, or having 1 substituentselected from R₁₂ and 0-3 substituents independently selected from F,Cl, Br, or I;

Substituted naphthyl is a naphthalene moiety either having 1-4substituents independently selected from F, Cl, Br, or I, or having 1substituent selected from R₁₂ and 0-3 substituents independentlyselected from F, Cl, Br, or I, where the substitution can beindependently on either only one ring or both rings of said naphthalenemoiety;

Alkyl is both straight- and branched-chain moieties having from 1-6carbon atoms;

Lower alkyl is both straight- and branched-chain moieties having from1-4 carbon atoms;

Halogenated alkyl is an alkyl moiety having from 1-6 carbon atoms andhaving 1 to (2n+1) substituent(s) independently selected from F, Cl, Br,or I where n is the maximum number of carbon atoms in the moiety;

Lower halogenated alkyl is an alkyl moiety having from 1-4 carbon atomsand having 1 to (2n+1) substituent(s) independently selected from F, Cl,Br, or I where n is the maximum number of carbon atoms in the moiety;

Substituted alkyl is an alkyl moiety from 1-6 carbon atoms and having0-3 substituents independently selected from F, Cl, Br, or I and furtherhaving 1 substituent selected from —OR₁₀, —SR₁₀, —N(R₁₀)₂, —C(O)R₁₀,—C(O)N(R₁₀)₂, —CN, —NR₁₀C(O)R₁₀, —S(O)₂N(R₁₀)₂, —NR₁₀S(O)₂R₁₀, —NO₂, R₇,R₉, phenyl, or phenyl having 1 substituent selected from R₂₀ and furtherhaving 0-3 substituents independently selected from F, Cl, Br, or I;

Lower substituted alkyl is lower alkyl having 0-3 substituentsindependently selected from F, Cl, Br, or I, and further having 1substituent selected from —OR₁₀, —SR₁₀, —N(R₁₀)₂, —C(O)R₁₀,—C(O)N(R₁₀)₂, —CN, —NR₁₀C(O)R₁₀, —S(O)₂N(R₁₀)₂, —NR₁₀S(O)₂R₁₀, —NO₂, orphenyl,

wherein each R₁₀ is independently H, lower alkyl, cycloalkyl,heterocycloalkyl, or phenyl,

wherein any lower alkyl, cycloalkyl, heterocycloalkyl, or phenyl isoptionally substituted with up to two halogens and up to one othersubstituent independently selected from —OR₁₁, —SR₁₁, —N(R₁₁)₂,—C(O)R₁₁, —C(O)N(R₁₁)₂, —CN, —CF₃, —NR₁₁C(O)R₁₁, —S(O)₂N(R₁₁)₂,—NR₁₁S(O)₂R₁₁, or —NO₂, and

wherein each R₁₁ is independently H, lower alkyl, lower cycloalkyl,heterocycloalkyl, lower halogenated alkyl, lower halogenated cycloalkyl,or halogenated heterocycloalkyl;

Alkenyl is straight- and branched-chain moieties having from 2-6 carbonatoms and having at least one carbon-carbon double bond;

Lower alkenyl is straight- and branched-chain moieties having from 2-4carbon atoms and having at least one carbon-carbon double bond;

Halogenated alkenyl is an unsaturated alkenyl moiety having from 2-6carbon atoms and having 1 to (2n−1) substituent(s) independentlyselected from F, Cl, Br, or I where n is the maximum number of carbonatoms in the moiety;

Lower halogenated alkenyl is an unsaturated alkenyl moiety having from2-4 carbon atoms and having 1 to (2n−1) substituent(s) independentlyselected from F, Cl, Br, or I where n is the maximum number of carbonatoms in the moiety;

Substituted alkenyl is an unsaturated alkenyl moiety having from 2-4carbon atoms and having 0-3 substituents independently selected from F,or Cl, and further having 1 substituent selected from R₇, R₉, —OR₁₀,—SR₁₀, —N(R₁₀)₂, —C(O)R₁₀, —C(O)N(R₁₀)₂, —NR₁₀C(O)R₁₀, —S(O)₂N(R₁₀)₂,—NR₁₀S(O)₂R₁₀, —CN, phenyl, or phenyl having 1 substituent selected fromR₂₀ and further having 0-3 substituents independently selected from F,Cl, Br, or I;

Lower substituted alkenyl is lower alkenyl having 0-3 substituentsindependently selected from F, or Cl, and further having 1 substituentselected from —OR₁₀, —SR₁₀, —N(R₁₀)₂, —C(O)R₁₀, —C(O)N(R₁₀)₂, —CN,—NR₁₀C(O)R₁₀, —S(O)₂N(R₁₀)₂, —NR₁₀S(O)₂R₁₀, —NO₂, or phenyl,

wherein each R₁₀ is independently H, lower alkyl, cycloalkyl,heterocycloalkyl, or phenyl,

wherein any lower alkyl, cycloalkyl, heterocycloalkyl, or phenyl isoptionally substituted with up to two halogens and up to one othersubstituent independently selected from —OR₁₁, —SR₁₁, —N(R₁₁)₂,—C(O)R₁₁, —C(O)N(R₁₁)₂, —CN, —CF₃, —NR₁₁C(O)R₁₁, —S(O)₂N(R₁₁)₂,—NR₁₁S(O)₂R₁₁, or —NO₂, and

wherein each R₁₁ is independently H, lower alkyl, lower cycloalkyl,heterocycloalkyl, lower halogenated alkyl, lower halogenated cycloalkyl,or halogenated heterocycloalkyl;

Alkynyl is straight- and branched-chained moieties having from 2-6carbon atoms and having at least one carbon-carbon triple bond;

Lower alkynyl is straight- and branched-chained moieties having from 2-4carbon atoms and having at least one carbon-carbon triple bond;

Halogenated alkynyl is an unsaturated alkynyl moiety having from 3-6carbon atoms and having 1 to (2n−3) substituent(s) independentlyselected from F, Cl, Br, or I where n is the maximum number of carbonatoms in the moiety;

Lower halogenated alkynyl is an unsaturated alkynyl moiety having from3-4 carbon atoms and having 1 to (2n−3) substituent(s) independentlyselected from F, Cl, Br, or I where n is the maximum number of carbonatoms in the moiety;

Substituted alkynyl is an unsaturated alkynyl moiety having from 3-6carbon atoms and having 0-3 substituents independently selected from F,or Cl, and further having 1 substituent selected from —R₇, —R₉, —OR₁₀,—SR₁₀, —N(R₁₀)₂, —C(O)R₁₀, —C(O)N(R₁₀)₂, —NR₁₀C(O)R₁₀, —S(O)₂N(R₁₀)₂,—NR₁₀S(O)₂R₁₀, —CN, phenyl, or phenyl having 1 substituent selected fromR₂₀ and further having 0-3 substituents independently selected from F,Cl, Br, or I;

Lower substituted alkynyl is lower alkynyl having 0-3 substituentsindependently selected from F, or Cl, and further having 1 substituentselected from —OR₁₀, —SR₁₀, —N(R₁₀)₂, —C(O)R₁₀, —C(O)N(R₁₀)₂, —CN,—NR₁₀C(O)R₁₀, —S(O)₂N(R₁₀)₂, —NR₁₀S(O)₂R₁₀, —NO₂, or phenyl,

wherein each R₁₀ is independently H, lower alkyl, cycloalkyl,heterocycloalkyl, or phenyl,

wherein any lower alkyl, cycloalkyl, heterocycloalkyl, or phenyl isoptionally substituted with up to two halogens and up to one othersubstituent independently selected from —OR₁₁, —SR₁₁, —N(R₁₁)₂,—C(O)R₁₁, —C(O)N(R₁₁)₂, —CN, —CF₃, —NR₁₁C(O)R₁₁, —S(O)₂N(R₁₁)₂,—NR₁₁S(O)₂R₁₁, or —NO₂, and

wherein each R₁₁ is independently H, lower alkyl, lower cycloalkyl,heterocycloalkyl, lower halogenated alkyl, lower halogenated cycloalkyl,or halogenated heterocycloalkyl;

Cycloalkyl is a cyclic alkyl moiety having from 3-6 carbon atoms;

Halogenated cycloalkyl is a cyclic moiety having from 3-6 carbon atomsand having 1-4 substituents independently selected from F, or Cl;

Substituted cycloalkyl is a cyclic moiety having from 3-6 carbon atomsand having 0-3 substituents independently selected from F, or Cl, andfurther having 1 substituent selected from —OR₁₀, —SR₁₀, —N(R₁₀)₂,—C(O)R₁₀, —CN, —C(O)N(R₁₀)₂, —NR₁₀C(O)R₁₀, —S(O)₂N(R₁₀)₂, —NR₁₀S(O)₂R₁₀,—NO₂, phenyl, or phenyl having 1 substituent selected from R₂₀ andfurther having 0-3 substituents independently selected from F, Cl, Br,or I;

Heterocycloalkyl is a cyclic moiety having 4-7 atoms with 1-2 atomswithin the ring being —S—, —N(R₁₉)—, or —O—;

Halogenated heterocycloalkyl is a cyclic moiety having from 4-7 atomswith 1-2 atoms within the ring being —S—, —N(R₁₉)—, or —O—, and having1-4 substituents independently selected from F, or Cl;

Substituted heterocycloalkyl is a cyclic moiety having from 4-7 atomswith 1-2 atoms within the ring being —S—, —N(R₁₉)—, or —O— and having0-3 substituents independently selected from F, or Cl, and furtherhaving 1 substituent selected from —OR₁₀, —SR₁₀, —N(R₁₀)₂, —C(O)R₁₀,—C(O)N(R₁₀)₂, —CN, —NR₁₀C(O)R₁₀, —NO₂, —S(O)₂N(R₁₀)₂, —NR₁₀S(O)₂R₁₀,phenyl, or phenyl having 1 substituent selected from R₂₀ and furtherhaving 0-3 substituents independently selected from F, Cl, Br, or I;

or pharmaceutical composition, pharmaceutically acceptable salt, racemicmixture, or pure enantiomer thereof useful to treat any one of orcombination of cognitive and attention deficit symptoms of Alzheimer's,neurodegeneration associated with diseases such as Alzheimer's disease,pre-senile dementia (mild cognitive impairment), senile dementia,schizophrenia, psychosis, attention deficit disorder, attention deficithyperactivity disorder, depression, anxiety, general anxiety disorder,post traumatic stress disorder, mood and affective disorders,amyotrophic lateral sclerosis, borderline personality disorder,traumatic brain injury, behavioral and cognitive problems in general andassociated with brain tumors, AIDS dementia complex, dementia associatedwith Down's syndrome, dementia associated with Lewy Bodies, Huntington'sdisease, Parkinson's disease, tardive dyskinesia, Pick's disease,dysregulation of food intake including bulemia and anorexia nervosa,withdrawal symptoms associated with smoking cessation and dependant drugcessation, Gilles de la Tourette's Syndrome, age-related maculardegeneration, glaucoma, neurodegeneration associated with glaucoma, orsymptoms associated with pain.

In another aspect, the invention includes methods of treating a mammalsuffering from schizophrenia or psychosis by administering compounds ofFormula I in conjunction with antipsychotic drugs. The compounds ofFormula I and the antipsychotic drugs can be administered simultaneouslyor at separate intervals. When administered simultaneously the compoundsof Formula I and the antipsychotic drugs can be incorporated into asingle pharmaceutical composition. Alternatively, two separatecompositions, i.e., one containing compounds of Formula I and the othercontaining antipsychotic drugs, can be administered simultaneously.

The present invention also includes the intermediates, the processes tomake them and the compounds of the present invention, pharmaceuticalcompositions containing the active compounds, and methods to treat theidentified diseases.

Abbreviations which are well known to one of ordinary skill in the artmay be used (e.g., “Ph” for phenyl, “Me” for methyl, “Et” for ethyl, “h”or “hr” for hour or hours, min for minute or minutes, and “rt” or “RT”for room temperature).

All temperatures are in degrees Centigrade.

Room temperature is within the range of 15-25 degrees Celsius.

AChR refers to acetylcholine receptor.

nAChR refers to nicotinic acetylcholine receptor.

Pre-senile dementia is also known as mild cognitive impairment.

5HT₃R refers to the serotonin-type 3 receptor.

α-btx refers to α-bungarotoxin.

FLIPR refers to a device marketed by Molecular Devices, Inc. designed toprecisely measure cellular fluorescence in a high throughput whole-cellassay. (Schroeder et. al., J. Biomolecular Screening, 1(2), p 75-80,1996).

TLC refers to thin-layer chromatography.

HPLC refers to high pressure liquid chromatography.

MeOH refers to methanol.

EtOH refers to ethanol.

IPA refers to isopropyl alcohol.

THF refers to tetrahydrofuran.

DMSO refers to dimethylsulfoxide.

DMF refers to N,N-dimethylformamide.

EtOAc refers to ethyl acetate.

TMS refers to tetramethylsilane.

TEA refers to triethylamine.

DIEA refers to N,N-diisopropylethylamine.

MLA refers to methyllycaconitine.

Ether refers to diethyl ether.

HATU refers to O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate.

CDI refers to carbonyl diimidazole.

NMO refers to N-methylmorpholine-N-oxide.

TPAP refers to tetrapropylammonium perruthenate.

Halogen is F, Cl, Br, or I.

Na₂SO₄ refers to sodium sulfate.

K₂CO₃ refers to potassium carbonate.

MgSO₄ refers to magnesium sulfate.

When Na₂SO₄, K₂CO₃, or MgSO₄ is used as a drying agent, it is anhydrous.

The carbon atom content of various hydrocarbon-containing moieties isindicated by a prefix designating the minimum and maximum number ofcarbon atoms in the moiety, i.e., the prefix C_(i-j) indicates a moietyof the integer “i” to the integer “j” carbon atoms, inclusive. Thus, forexample, C₁₋₆ alkyl refers to alkyl of one to six carbon atoms.

Non-inclusive examples of heteroaryl compounds that fall within thedefinition of R₇ and R₉ include, but are not limited to, thienyl,benzothienyl, pyridyl, thiazolyl, quinolyl, pyrazinyl, pyrimidyl,imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl,benzisothiazolyl, benzisoxazolyl, benzimidazolyl, indolyl, benzoxazolyl,pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, pyrrolyl,isoquinolinyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl,pydridazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, furazanyl,benzofurazanyl, benzothiophenyl, benzothiazolyl, quinazolinyl,quinoxalinyl, naphthridinyl, and furopyridinyl.

Non-inclusive examples of heterocycloalkyl include, but are not limitedto, tetrahydrofurano, tetrahydropyrano, morpholino, pyrrolidino,piperidino, piperazine, azetidino, azetidinono, oxindolo,dihydroimidazolo, and pyrrolidinono

Mammal denotes human and other mammals.

Brine refers to an aqueous saturated sodium chloride solution.

Equ means molar equivalents.

IR refers to infrared spectroscopy.

Lv refers to leaving groups within a molecule, including Cl, OH, ormixed anhydride.

NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemicalshifts are reported in ppm (δ) downfield from TMS.

MS refers to mass spectrometry expressed as m/e or mass/charge unit.HRMS refers to high resolution mass spectrometry expressed as m/e ormass/charge unit. [M+H]⁺ refers to an ion composed of the parent plus aproton. [M−H]⁻ refers to an ion composed of the parent minus a proton.[M+Na]⁺ refers to an ion composed of the parent plus a sodium ion.[M+K]⁺ refers to an ion composed of the parent plus a potassium ion. EIrefers to electron impact. ESI refers to electrospray ionization. CIrefers to chemical ionization. FAB refers to fast atom bombardment.

Compounds of the present invention may be in the form ofpharmaceutically acceptable salts. The term “pharmaceutically acceptablesalts” refers to salts prepared from pharmaceutically acceptablenon-toxic bases including inorganic bases and organic bases, and saltsprepared from inorganic acids, and organic acids. Salts derived frominorganic bases include aluminum, ammonium, calcium, ferric, ferrous,lithium, magnesium, potassium, sodium, zinc, and the like. Salts derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, such as arginine,betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, and the like. Salts derived from inorganic acids includesalts of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuricacid, phosphoric acid, phosphorous acid and the like. Salts derived frompharmaceutically acceptable organic non-toxic acids include salts ofC₁₋₆ alkyl carboxylic acids, di-carboxylic acids, and tri-carboxylicacids such as acetic acid, propionic acid, fumaric acid, succinic acid,tartaric acid, maleic acid, adipic acid, and citric acid, and aryl andalkyl sulfonic acids such as toluene sulfonic acids and the like.

By the term “effective amount” of a compound as provided herein is meanta nontoxic but sufficient amount of the compound(s) to provide thedesired effect. As pointed out below, the exact amount required willvary from subject to subject, depending on the species, age, and generalcondition of the subject, the severity of the disease that is beingtreated, the particular compound(s) used, the mode of administration,and the like. Thus, it is not possible to specify an exact “effectiveamount.” However, an appropriate effective amount may be determined byone of ordinary skill in the art using only routine experimentation.

The amount of therapeutically effective compound(s) that is administeredand the dosage regimen for treating a disease condition with thecompounds and/or compositions of this invention depends on a variety offactors, including the age, weight, sex and medical condition of thesubject, the severity of the disease, the route and frequency ofadministration, and the particular compound(s) employed, and thus mayvary widely. The compositions contain well know carriers and excipientsin addition to a therapeutically effective amount of compounds ofFormula I. The pharmaceutical compositions may contain active ingredientin the range of about 0.001 to 100 mg/kg/day for an adult, preferably inthe range of about 0.1 to 50 mg/kg/day for an adult. A total daily doseof about 1 to 1000 mg of active ingredient may be appropriate for anadult. The daily dose can be administered in one to four doses per day.

In addition to the compound(s) of Formula I, the composition fortherapeutic use may also comprise one or more non-toxic,pharmaceutically acceptable carrier materials or excipients. The term“carrier” material or “excipient” herein means any substance, not itselfa therapeutic agent, used as a carrier and/or diluent and/or adjuvant,or vehicle for delivery of a therapeutic agent to a subject or added toa pharmaceutical composition to improve its handling or storageproperties or to permit or facilitate formation of a dose unit of thecomposition into a discrete article such as a capsule or tablet suitablefor oral administration. Excipients can include, by way of illustrationand not limitation, diluents, disintegrants, binding agents, adhesives,wetting agents, polymers, lubricants, glidants, substances added to maskor counteract a disagreeable taste or odor, flavors, dyes, fragrances,and substances added to improve appearance of the composition.Acceptable excipients include lactose, sucrose, starch powder, celluloseesters of alkanoic acids, cellulose alkyl esters, talc, stearic acid,magnesium stearate, magnesium oxide, sodium and calcium salts ofphosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate,polyvinyl-pyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation as may be provided in adispersion of active compound in hydroxypropyl-methyl cellulose, orother methods known to those skilled in the art. For oraladministration, the pharmaceutical composition may be in the form of,for example, a tablet, capsule, suspension or liquid. If desired, otheractive ingredients may be included in the composition.

In addition to the oral dosing, noted above, the compositions of thepresent invention may be administered by any suitable route, in the formof a pharmaceutical composition adapted to such a route, and in a doseeffective for the treatment intended. The compositions may, for example,be administered parenterally, e.g., intravascularly, intraperitoneally,subcutaneously, or intramuscularly. For parenteral administration,saline solution, dextrose solution, or water may be used as a suitablecarrier. Formulations for parenteral administration may be in the formof aqueous or non-aqueous isotonic sterile injection solutions orsuspensions. These solutions and suspensions may be prepared fromsterile powders or granules having one or more of the carriers ordiluents mentioned for use in the formulations for oral administration.The compounds may be dissolved in water, polyethylene glycol, propyleneglycol, EtOH, corn oil, cottonseed oil, peanut oil, sesame oil, benzylalcohol, sodium chloride, and/or various buffers. Other adjuvants andmodes of administration are well and widely known in the pharmaceuticalart.

The serotonin type 3 receptor (5HT₃R) is a member of a superfamily ofligand-gated ion channels, which includes the muscle and neuronal nAChR,the glycine receptor, and the γ-aminobutyric acid type A receptor. Likethe other members of this receptor superfamily, the 5HT₃R exhibits alarge degree of sequence homology with α7 nAChR but functionally the twoligand-gated ion channels are very different. For example, α7 nAChR israpidly inactivated, is highly permeable to calcium and is activated byacetylcholine and nicotine. On the other hand, 5HT₃R is inactivatedslowly, is relatively impermeable to calcium and is activated byserotonin. These experiments suggest that the α7 nAChR and 5HT₃Rproteins have some degree of homology, but function very differently.Indeed the pharmacology of the channels is very different. For example,Ondansetron, a highly selective 5HT₃R antagonist, has little activity atthe α7 nAChR. The converse is also true. For example, GTS-21, a highlyselective α7 nAChR agonist, has little activity at the 5HT₃R.

α7 nAChR is a ligand-gated Ca⁺⁺ channel formed by a homopentamer of α7subunits. Previous studies have established that α-bungarotoxin ((α-btx)binds selectively to this homopetameric, α7 nAChR subtype, and that α7nAChR has a high affinity binding site for both α-btx andmethyllycaconitine (MLA). α7 nAChR is expressed at high levels in thehippocampus, ventral tegmental area and ascending cholinergicprojections from nucleus basilis to thalamocortical areas. α7 nAChRagonists increase neurotransmitter release, and increase cognition,arousal, attention, learning and memory.

Data from human and animal pharmacological studies establish thatnicotinic cholinergic neuronal pathways control many important aspectsof cognitive function including attention, learning and memory (Levin,E. D., Psychopharmacology, 108:417-31, 1992; Levin, E. D. and Simon B.B., Psychopharmacology, 138:217-30, 1998). For example, it is well knownthat nicotine increases cognition and attention in humans. ABT-418, acompound that activates α4β2 and α7 nAChR, improves cognition andattention in clinical trials of Alzheimer's disease andattention-deficit disorders (Potter, A. et. al., Psychopharmacology(Berl)., 142(4):334-42, March 1999; Wilens, T. E. et. al., Am. J.Psychiatry, 156(12):1931-7, December 1999). It is also clear thatnicotine and selective but weak α7 nAChR agonists increase cognition andattention in rodents and non-human primates.

Schizophrenia is a complex multifactorial illness caused by genetic andnon-genetic risk factors that produce a constellation of positive andnegative symptoms. The positive symptoms include delusions andhallucinations and the negative symptoms include deficits in affect,attention, cognition and information processing. No single biologicalelement has emerged as a dominant pathogenic factor in this disease.Indeed, it is likely that schizophrenia is a syndrome that is producedby the combination of many low penetrance risk factors. Pharmacologicalstudies established that dopamine receptor antagonists are efficaciousin treating the overt psychotic features (positive symptoms) ofschizophrenia such as hallucinations and delusions. Clozapine, an “atypical” antipsychotic drug, is novel because it is effective intreating both the positive and some of the negative symptoms of thisdisease. Clozapine's utility as a drug is greatly limited becausecontinued use leads to an increased risk of agranulocytosis and seizure.No other antipsychotic drug is effective in treating the negativesymptoms of schizophrenia. This is significant because the restorationof cognitive functioning is the best predictor of a successful clinicaland functional outcome of schizophrenic patients (Green, M. F., Am JPsychiatry, 153:321-30, 1996). By extension, it is clear that betterdrugs are needed to treat the cognitive disorders of schizophrenia inorder to restore a better state of mental health to patients with thisdisorder.

One aspect of the cognitive deficit of schizophrenia can be measured byusing the auditory event-related potential (P50) test of sensory gating.In this test, electroencepholographic (EEG) recordings of neuronalactivity of the hippocampus are used to measure the subject's responseto a series of auditory “clicks” (Adler, L. E. et. al., Biol.Psychiatry, 46:8-18, 1999). Normal individuals respond to the firstclick with greater degree than to the second click. In general,schizophrenics and schizotypal patients respond to both clicks nearlythe same (Cullum, C. M. et. al., Schizophr. Res., 10:131-41, 1993).These data reflect a schizophrenic's inability to “filter” or ignoreunimportant information. The sensory gating deficit appears to be one ofthe key pathological features of this disease (Cadenhead, K. S. et. al.,Am. J. Psychiatry, 157:55-9, 2000). Multiple studies show that nicotinenormalizes the sensory deficit of schizophrenia (Adler, L. E. et. al.,Am. J. Psychiatry, 150:1856-61, 1993). Pharmacological studies indicatethat nicotine's effect on sensory gating is via the α7 nAChR (Adler, L.E. et. al., Schizophr. Bull., 24:189-202, 1998). Indeed, the biochemicaldata indicate that schizophrenics have 50% fewer of α7 nAChR receptorsin the hippocampus, thus giving a rationale to partial loss of α7 nAChRfunctionality (Freedman, R. et. al., Biol. Psychiatry, 38:22-33, 1995).Interestingly, genetic data indicate that a polymorphism in the promoterregion of the α7 nAChR gene is strongly associated with the sensorygating deficit in schizophrenia (Freedman, R. et. al., Proc. Nat'l Acad.Sci. USA, 94(2):587-92, 1997; Myles-Worsley, M. et. al., Am. J. Med.Genet, 88(5):544-50, 1999). To date, no mutation in the coding region ofthe α7 nAChR has been identified. Thus, schizophrenics express the sameα7 nAChR as non-schizophrenics.

Selective α7 nAChR agonists may be found using a functional assay onFLIPR (see WO 00/73431 A2). FLIPR is designed to read the fluorescentsignal from each well of a 96 or 384 well plate as fast as twice asecond for up to 30 minutes. This assay may be used to accuratelymeasure the functional pharmacology of α7 nAChR and 5HT₃R. To conductsuch an assay, one uses cell lines that expressed functional forms ofthe α7 nAChR using the α7/5-HT₃ channel as the drug target and celllines that expressed functional 5HT₃R. In both cases, the ligand-gatedion channel was expressed in SH-EP1 cells. Both ion channels can producerobust signal in the FLIPR assay.

The compounds of the present invention are α7 nAChR agonists and may beused to treat a wide variety of diseases. For example, they may be usedin treating schizophrenia, or psychosis.

Schizophrenia is a disease having multiple aspects. Currently availabledrugs are generally aimed at controlling the positive aspects ofschizophrenia, such as delusions. One drug, Clozapine, is aimed at abroader spectrum of symptoms associated with schizophrenia. This drughas many side effects and is thus not suitable for many patients. Thus,there is a need for a drug to treat the cognitive and attention deficitsassociated with schizophrenia. Similarly, there is a need for a drug totreat the cognitive and attention deficits associated withschizoaffective disorders, or similar symptoms found in the relatives ofschizophrenic patients.

Psychosis is a mental disorder characterized by gross impairment in thepatient's perception of reality. The patient may suffer from delusions,and hallucinations, and may be incoherent in speech. His behavior may beagitated and is often incomprehensible to those around him. In the past,the term psychosis has been applied to many conditions that do not meetthe stricter definition given above. For example, mood disorders werenamed as psychoses.

There are a variety of antipsychotic drugs. The conventionalantipsychotic drugs include Chlorpromazine, Fluphenazine, Haloperidol,Loxapine, Mesoridazine, Molindone, Perphenazine, Pimozide, Thioridazine,Thiothixene, and Trifluoperazine. These drugs all have an affinity forthe dopamine 2 receptor.

These conventional antipsychotic drugs have several side effects,including sedation, weight gain, tremors, elevated prolactin levels,akathisia (motor restlessness), dystonia and muscle stiffness. Thesedrugs may also cause tardive dyskinesia. Unfortunately, only about 70%of patients with schizophrenia respond to conventional antipsychoticdrugs. For these patients, a typical antipsychotic drugs are available.

A typical antipsychotic drugs generally are able to alleviate positivesymptoms of psychosis while also improving negative symptoms of thepsychosis to a greater degree than conventional antipsychotics. Thesedrugs may improve neurocognitive deficits. Extrapyramidal (motor) sideeffects are not as likely to occur with the a typical antipsychoticdrugs, and thus, these a typical antipsychotic drugs have a lower riskof producing tardive dyskinesia. Finally these a typical antipsychoticdrugs cause little or no elevation of prolactin. Unfortunately, thesedrugs are not free of side effects. Although these drugs each producedifferent side effects, as a group the side effects include:agranulocytosis; increased risk of seizures, weight gain, somnolence,dizziness, tachycardia, decreased ejaculatory volume, and mildprolongation of QTc interval.

In a combination therapy to treat multiple symptoms of diseases such asschizophrenia, the compounds of Formula I and the anti-psychotic drugscan be administered simultaneously or at separate intervals. Whenadministered simultaneously the compounds of Formula I and theanti-psychotic drugs can be incorporated into a single pharmaceuticalcomposition, e.g., a pharmaceutical combination therapy composition.Alternatively, two separate compositions, i.e., one containing compoundsof Formula I and the other containing anti-psychotic drugs, can beadministered simultaneously. Examples of anti-psychotic drugs, inaddition to those listed above, include, but are not limited to,Thorazine, Mellaril, Trilafon, Navane, Stelazine, Permitil, Prolixin,Risperdal, Zyprexa, Seroquel, ZELDOX, Acetophenazine, Carphenazine,Chlorprothixene, Droperidol, Loxapine, Mesoridazine, Molindone,Ondansetron, Pimozide, Prochlorperazine, and Promazine.

A pharmaceutical combination therapy composition can includetherapeutically effective amounts of the compounds of Formula I and atherapeutically effective amount of anti-psychotic drugs. Thesecompositions may be formulated with common excipients, diluents orcarriers, and compressed into tablets, or formulated elixirs orsolutions for convenient oral administration or administered byintramuscular intravenous routes. The compounds can be administeredrectally, topically, orally, sublingually, or parenterally and maybeformulated as sustained relief dosage forms and the like.

When separately administered, therapeutically effective amounts ofcompositions containing compounds of Formula I and anti-psychotic drugsare administered on a different schedule. One may be administered beforethe other as long as the time between the two administrations fallswithin a therapeutically effective interval. A therapeutically effectiveinterval is a period of time beginning when one of either (a) thecompounds of Formula I, or (b) the anti-psychotic drugs is administeredto a human and ending at the limit of the beneficial effect in thetreatment of schizophrenia or psychosis of the combination of (a) and(b). The methods of administration of the compounds of Formula I and theanti-psychotic drugs may vary. Thus, either agent or both agents may beadministered rectally, topically, orally, sublingually, or parenterally.

As discussed, the compounds of the present invention are α7 nAChRagonists. Therefore, as another aspect of the present invention, thecompounds of the present invention may be used to treat a variety ofdiseases including cognitive and attention deficit symptoms ofAlzheimer's, neurodegeneration associated with diseases such asAlzheimer's disease, pre-senile dementia (also known as mild cognitiveimpairment), and senile dementia.

Alzheimer's disease has many aspects, including cognitive and attentiondeficits. Currently, these deficits are treated with cholinesteraseinhibitors. These inhibitors slow the break down of acetylcholine, andthereby provide a general nonspecific increase in the activity of thecholinergic nervous system. Since the drugs are nonspecific, they have awide variety of side effects. Thus, there is a need for a drug thatstimulates a portion of the cholinergic pathways and thereby providesimprovement in the cognitive and attention deficits associated withAlzheimer's disease without the side effects created by nonspecificstimulation of the cholinergic pathways.

Neurodegeneration is a common problem associated with diseases such asAlzheimer's disease. While the current drugs treat some of the symptomsof this disease, they do not control the underlying pathology of thedisease. Accordingly, it would be desirable to provide a drug that canslow the progress of Alzheimer's disease.

Pre-senile dementia (mild cognitive impairment) concerns memoryimpairment rather than attention deficit problems and otherwiseunimpaired cognitive functioning. Mild cognitive impairment isdistinguished from senile dementia in that mild cognitive impairmentinvolves a more persistent and troublesome problem of memory loss forthe age of the patient. There currently is no medication specificallyidentified for treatment of mild cognitive impairment, due somewhat tothe newness of identifying the disease. Therefore, there is a need for adrug to treat the memory problems associated with mild cognitiveimpairment.

Senile dementia is not a single disease state. However, the conditionsclassified under this name frequently include cognitive and attentiondeficits. Generally, these deficits are not treated. Accordingly, thereis a need for a drug that provides improvement in the cognitive andattention deficits associated with senile dementia.

As discussed, the compounds of the present invention are α7 nAChRagonists. Therefore, yet other diseases to be treated with compounds ofthe present invention include treating the cognitive and attentiondeficits as well as the neurodegeneration associated with any one ormore or combination of the following: attention deficit disorder,attention deficit hyperactivity disorder, depression, anxiety, generalanxiety disorder, post traumatic stress disorder, mood and affectivedisorders, amyotrophic lateral sclerosis, borderline personalitydisorder, traumatic brain injury, behavioral and cognitive problemsassociated with brain tumors, AIDS dementia complex, dementia associatedwith Down's syndrome, dementia associated with Lewy Bodies, Huntington'sdisease, Parkinson's disease, tardive dyskinesia, Pick's disease,dysregulation of food intake including bulemia and anorexia nervosa,withdrawal symptoms associated with smoking cessation and dependant drugcessation, Gilles de la Tourette's Syndrome, age-related maculardegeneration, glaucoma, neurodegeneration associated with glaucoma, orsymptoms associated with pain.

Attention deficit disorder is generally treated with methylphenidate, anamphetamine-like molecule that has some potential for abuse.Accordingly, it would be desirable to provide a drug that treatsattention deficit disorder while having fewer side effects than thecurrently used drug.

Attention deficit hyperactivity disorder, otherwise known as ADHD, is aneurobehavioral disorder affecting 3-5% of all American children. ADHDconcerns cognitive alone or both cognitive and behavioral actions byinterfering with a person's ability to stay on a task and to exerciseage-appropriate inhibition. Several types of ADHD exist: a predominantlyinattentive subtype, a predominantly hyperactive-impulsive subtype, anda combined subtype. Treatment may include medications such asmethylphenidate, dextroamphetamine, or pemoline, which act to decreaseimpulsivity and hyperactivity and to increase attention. No “cure” forADHD currently exists. Children with the disorder seldom outgrow it;therefore, there is a need for appropriate medicaments.

Depression is a mood disorder of varying lengths of normally severalmonths to more than two years and of varying degrees of feelingsinvolving sadness, despair, and discouragement. The heterocyclicantidepressants (HCA's) are currently the largest class ofantidepressants, but monoamine oxidase inhibitors (MAOI's) are used inparticular types of depression. Common side effects from HCA's aresedation and weight gain. In elderly patients with organic braindisease, the side effects from HCA's can also include seizures andbehavioral symptoms. The main side effects from using MAOI's occur fromdietary and drug interactions. Therefore, agents with fewer side effectswould be useful.

Anxiety disorders (disorders with prominent anxiety or phobicavoidance), represent an area of unmet medical needs in the treatment ofpsychiatric illness. See Diagnostic & Statistical Manual of MentalDisorders, IV (1994), pp 393-394, for various disease forms of anxiety.

General anxiety disorder (GAD) occurs when a person worries about thingssuch as family, health, or work when there is no reason to worry and isunable not to worry. About 3 to 4% of the U.S. population has GAD duringthe course of a year. GAD most often strikes people in childhood oradolescence, but can begin in adulthood, too. It affects women moreoften than men. Currently, treatment involves cognitive-behavioraltherapy, relaxation techniques, and biofeedback to control muscletension and medications such as benzodiazepines, imipramine, andbuspirone. These drugs are effective but all have side-effectliabilities. Therefore, there is a need of a pharmaceutical agent toaddress the symptoms with fewer side effects.

Anxiety also includes post-traumatic stress disorder (PTSD), which is aform of anxiety triggered by memories of a traumatic event that directlyaffected the patient or that the patient may have witnessed. Thedisorder commonly affects survivors of traumatic events including sexualassault, physical assault, war, torture, natural disasters, anautomobile accident, an airplane crash, a hostage situation, or a deathcamp. The affliction also can affect rescue workers at an airplane crashor a mass shooting, someone who witnessed a tragic accident or someonewho has unexpectedly lost a loved one. Treatment for PTSD includescognitive-behavioral therapy, group psychotherapy, and medications suchas Clonazepam, Lorazepam and selective serotonin-reuptake inhibitorssuch as Fluoxetine, Sertraline, Paroxetine, Citalopram and Fluvoxamine.These medications help control anxiety as well as depression. Variousforms of exposure therapy (such as systemic desensitization and imaginalflooding) have all been used with PTSD patients. Exposure treatment forPTSD involves repeated reliving of the trauma, under controlledconditions, with the aim of facilitating the processing of the trauma.Therefore, there is a need for better pharmaceutical agents to treatpost traumatic stress disorder.

Mood and affective disorders fall within a large group of diseases,including monopolar depression and bi-polar mood disorder. Thesediseases are treated with three major classes of compounds. The firstgroup is the heterocyclic antidepressant (HCA's). This group includesthe well-known tricyclic antidepressants. The second group of compoundsused to treat mood disorders is the monoamine oxidase inhibitors(MAOI's) that are used in particular types of diseases. The third drugis lithium. Common side effects from HCA's are sedation and weight gain.In elderly patients with organic brain disease, the side effects ofHCA's can also include seizures and behavioral symptoms. The main sideeffects from using MAOI's occur from dietary and drug interactions.Benign side effects from the use of lithium include, but are not limitedto, weight gain, nausea, diarrhea, polyuria, polydipsia, and tremor.Toxic side effects from lithium can include persistent headache, mentalconfusion, and may reach seizures and cardiac arrhythmias. Therefore,agents with less side effects or interactions with food or othermedications would be useful.

Borderline personality disorder, although not as well known as bipolardisorder, is more common. People having borderline personality disordersuffer from a disorder of emotion regulation. Pharmaceutical agents areused to treat specific symptoms, such as depression or thinkingdistortions.

Acquired immune deficiency syndrome (AIDS) results from an infectionwith the human immunodeficiency virus (HIV). This virus attacks selectedcells and impairs the proper function of the immune, nervous, and othersystems. HIV infection can cause other problems such as, but not limitedto, difficulties in thinking, otherwise known as AIDS dementia complex.Therefore, there is a need to drugs to relieve the confusion and mentaldecline of persons with AIDS.

Amyotrophic lateral sclerosis, also known as Lou Gehrig's disease,belongs to a class of disorders known as motor neuron diseases whereinspecific nerve cells in the brain and spinal cord gradually degenerateto negatively affect the control of voluntary movement. Currently, thereis no cure for amyotrophic lateral sclerosis although patients mayreceive treatment from some of their symptoms and although Riluzole hasbeen shown to prolong the survival of patients. Therefore, there is aneed for a pharmaceutical agent to treat this disease.

Traumatic brain injury occurs when the brain is damaged from a suddenphysical assault on the head. Symptoms of the traumatic brain injuryinclude confusion and other cognitive problems. Therefore, there is aneed to address the symptoms of confusion and other cognitive problems.

Brain tumors are abnormal growths of tissue found inside of the skull.Symptoms of brain tumors include behavioral and cognitive problems.Surgery, radiation, and chemotherapy are used to treat the tumor, butother agents are necessary to address associated symptoms. Therefore,there is a need to address the symptoms of behavioral and cognitiveproblems.

Persons with Down's syndrome have in all or at least some of their cellsan extra, critical portion of the number 21 chromosome. Adults who haveDown's syndrome are known to be at risk for Alzheimer-type dementia.Currently, there is no proven treatment for Down's syndrome. Therefore,there is a need to address the dementia associated with Down's syndrome.

Genetically programmed degeneration of neurons in certain areas of thebrain cause Huntington's disease. Early symptoms of Huntington's diseaseinclude mood swings, or trouble learning new things or remembering afact. Most drugs used to treat the symptoms of Huntington's disease haveside effects such as fatigue, restlessness, or hyperexcitability.Currently, there is no treatment to stop or reverse the progression ofHuntington's disease. Therefore, there is a need of a pharmaceuticalagent to address the symptoms with fewer side effects.

Dementia with Lewy Bodies is a neurodegenerative disorder involvingabnormal structures known as Lewy bodies found in certain areas of thebrain. Symptoms of dementia with Lewy bodies include, but are notlimited to, fluctuating cognitive impairment with episodic delirium.Currently, treatment concerns addressing the parkinsonian andpsychiatric symptoms. However, medicine to control tremors or loss ofmuscle movement may actually accentuate the underlying disease ofdementia with Lewy bodies. Therefore, there is a need of apharmaceutical agent to treat dementia with Lewy bodies.

Parkinson's disease is a neurological disorder characterized by tremor,hypokinesia, and muscular rigidity. Currently, there is no treatment tostop the progression of the disease. Therefore, there is a need of apharmaceutical agent to address Parkinson's.

Tardive dyskinesia is associated with the use of conventionalantipsychotic drugs. This disease is characterized by involuntarymovements most often manifested by puckering of the lips and tongueand/or writhing of the arms or legs. The incidence of tardive dyskinesiais about 5% per year of drug exposure among patients taking conventionalantipsychotic drugs. In about 2% of persons with the disease, tardivedyskinesia is severely disfiguring. Currently, there is no generalizedtreatment for tardive dyskinesia. Furthermore, the removal of theeffect-causing drugs is not always an option due to underlying problems.Therefore, there is a need for a pharmaceutical agent to address thesymptoms of tardive dyskinesia.

Pick's disease results from a slowly progressive deterioration of socialskills and changes in personality with the resulting symptoms beingimpairment of intellect, memory, and language. Common symptoms includememory loss, lack of spontaneity, difficulty in thinking orconcentrating, and speech disturbances. Currently, there is no specifictreatment or cure for Pick's disease but some symptoms can be treatedwith cholinergic and serotonin-boosting antidepressants. In addition,antipsychotic medications may alleviate symptoms in FTD patients who areexperiencing delusions or hallucinations. Therefore, there is a need fora pharmaceutical agent to treat the progressive deterioration of socialskills and changes in personality and to address the symptoms with fewerside effects.

Dysregulation of food intake associated with eating disease, includingbulemia nervosa and anorexia nervosa, involve neurophysiologicalpathways. Anorexia nervosa is hard to treat due to patients not enteringor remaining in after entering programs. Currently, there is noeffective treatment for persons suffering from severe anorexia nervosa.Cognitive behavioral therapy has helped patients suffering from bulemianervosa; however, the response rate is only about 50% and currenttreatment does not adequately address emotional regulation. Therefore,there is a need for pharmaceutical agents to address neurophysiologicalproblems underlying diseases of dysregulation of food intake.

Cigarette smoking has been recognized as a major public health problemfor a long time. However, in spite of the public awareness of healthhazard, the smoking habit remains extraordinarily persistent anddifficult to break. There are many treatment methods available, and yetpeople continue to smoke. Administration of nicotine transdermally, orin a chewing gum base is common treatments. However, nicotine has alarge number of actions in the body, and thus can have many sideeffects. It is clear that there is both a need and a demand of longstanding for a convenient and relatively easy method for aiding smokersin reducing or eliminating cigarette consumption. A drug that couldselectively stimulate only certain of the nicotinic receptors would beuseful in smoke cessation programs.

Smoke cessation programs may involve oral dosing of the drug of choice.The drug may be in the form of tablets. However, it is preferred toadminister the daily dose over the waking hours, by administration of aseries of incremental doses during the day. The preferred method of suchadministration is a slowly dissolving lozenge, troche, or chewing gum,in which the drug is dispersed. Another drug in treating nicotineaddiction is Zyban. This is not a nicotine replacement, as are the gumand patch. Rather, this works on other areas of the brain, and itseffectiveness is to help control nicotine craving or thoughts aboutcigarette use in people trying to quit. Zyban is not very effective andeffective drugs are needed to assist smokers in their desire to stopsmoking. These drugs may be administered transdermally through the useof skin patches. In certain cases, the drugs may be administered bysubcutaneous injection, especially if sustained release formulations areused.

Drug use and dependence is a complex phenomenon, which cannot beencapsulated within a single definition. Different drugs have differenteffects, and therefore different types of dependence. Drug dependencehas two basic causes, that is, tolerance and physical dependence.Tolerance exists when the user must take progressively larger doses toproduce the effect originally achieved with smaller doses. Physicaldependence exists when the user has developed a state of physiologicadaptation to a drug, and there is a withdrawal (abstinence) syndromewhen the drug is no longer taken. A withdrawal syndrome can occur eitherwhen the drug is discontinued or when an antagonist displaces the drugfrom its binding site on cell receptors, thereby counteracting itseffect. Drug dependence does not always require physical dependence.

In addition drug dependence often involves psychological dependence,that is, a feeling of pleasure or satisfaction when taking the drug.These feelings lead the user to repeat the drug experience or to avoidthe displeasure of being deprived of the drug. Drugs that produce strongphysical dependence, such as nicotine, heroin and alcohol are oftenabused, and the pattern of dependence is difficult to break. Drugs thatproduce dependence act on the CNS and generally reduce anxiety andtension; produce elation, euphoria, or other pleasurable mood changes;provide the user feelings of increased mental and physical ability; oralter sensory perception in some pleasurable manner. Among the drugsthat are commonly abused are ethyl alcohol, opioids, anxiolytics,hypnotics, cannabis (marijuana), cocaine, amphetamines, andhallucinogens. The current treatment for drug-addicted people ofteninvolves a combination of behavioral therapies and medications.Medications, such as methadone or LAAM (levo-alpha-acetyl-methadol), areeffective in suppressing the withdrawal symptoms and drug cravingassociated with narcotic addiction, thus reducing illicit drug use andimproving the chances of the individual remaining in treatment. Theprimary medically assisted withdrawal method for narcotic addiction isto switch the patient to a comparable drug that produces milderwithdrawal symptoms, and then gradually taper off the substitutemedication. The medication used most often is methadone, taken orallyonce a day. Patients are started on the lowest dose that prevents themore severe signs of withdrawal and then the dose is gradually reduced.Substitutes can be used also for withdrawal from sedatives. Patients canbe switched to long-acting sedatives, such as diazepam or phenobarbital,which are then gradually reduced.

Gilles de la Tourette's Syndrome is an inherited neurological disorder.The disorder is characterized by uncontrollable vocal sounds called ticsand involuntary movements. The symptoms generally manifest in anindividual before the person is 18 years of age. The movement disordermay begin with simple tics that progress to multiple complex tics,including respiratory and vocal ones. Vocal tics may begin as gruntingor barking noises and evolve into compulsive utterances. Coprolalia(involuntary scatologic utterances) occurs in 50% of patients. Severetics and coprolalia may be physically and socially disabling. Tics tendto be more complex than myoclonus, but less flowing than choreicmovements, from which they must be differentiated. The patient mayvoluntarily suppress them for seconds or minutes.

Currently simple tics are often treated with benzodiazepines. For simpleand complex tics, Clonidine may be used. Long-term use of Clonidine doesnot cause tardive dyskinesia; its limiting adverse effect ishypotension. In more severe cases, antipsychotics, such as Haloperidolmay be required, but side effects of dysphoria, parkinsonism, akathisia,and tardive dyskinesia may limit use of such antipsychotics. There is aneed for safe and effective methods for treating this syndrome.

Age-related macular degeneration (AMD) is a common eye disease of themacula which is a tiny area in the retina that helps produce sharp,central vision required for “straight ahead” activities that includereading and driving. Persons with AMD lose their clear, central vision.AMD takes two forms: wet and dry. In dry AMD, there is a slow breakdownof light-sensing cells in the macula. There currently is no cure for dryAMD. In wet AMD, new, fragile blood vessels growing beneath the maculaas dry AMD worsens and these vessels often leak blood and fluid to causerapid damage to the macula quickly leading to the loss of centralvision. Laser surgery can treat some cases of wet AMD. Therefore, thereis a need of a pharmaceutical agent to address AMD.

Glaucoma is within a group of diseases occurs from an increase inintraocular pressure causing pathological changes in the optical diskand negatively affects the field of vision. Medicaments to treatglaucoma either decrease the amount of fluid entering the eye orincrease drainage of fluids from the eye in order to decreaseintraocular pressure. However, current drugs have drawbacks such as notworking over time or causing side effects so the eye-care professionalhas to either prescribe other drugs or modify the prescription of thedrug being used. There is a need for safe and effective methods fortreating problems manifesting into glaucoma.

Ischemic periods in glaucoma cause release of excitotoxic amino acidsand stimulate inducible form of nitric oxide synthase (iNOS) leading toneurodegeneration. Alpha 7 nicotinic agonists may stimulate the releaseof inhibitory amino acids such as GABA which will dampenhyperexcitablity. Alpha 7 nicotinic agonists are also directlyneuroprotective on neuronal cell bodies. Thus alpha 7 nicotinic agonistshave the potential to be neuroprotective in glaucoma.

Persons afflicted with pain often have what is referred to as the“terrible triad” of suffering from the pain, resulting in sleeplessnessand sadness, all of which are hard on the afflicted individual and thatindividual's family. Pain can manifest itself in various forms,including, but not limited to, headaches of all severity, back pain,neurogenic, and pain from other ailments such as arthritis and cancerfrom its existence or from therapy to eradicate it. Pain can be eitherchronic (persistent pain for months or years) or acute (short-lived,immediate pain to inform the person of possible injury and need oftreatment). Persons suffering from pain respond differently toindividual therapies with varying degrees of success. There is a needfor safe and effective methods for treating pain.

Finally, the compounds of the present invention may be used incombination therapy with typical and a typical anti-psychotic drugs(also called an anti-psychotic agent). All compounds within the presentinvention are useful for and may also be used in combination with eachother to prepare pharmaceutical compositions. Such combination therapylowers the effective dose of the anti-psychotic drug and thereby reducesthe side effects of the anti-psychotic drugs. Some typicalanti-psychotic drugs that may be used in the practice of the inventioninclude Haldol. Some a typical anti-psychotic drugs include Ziprasidone,Olanzapine, Resperidone, and Quetiapine.

Compounds of Formula I can be prepared as shown in Scheme 1. The keystep in the preparation of this class of compounds is the coupling of anamino-azabicyclic moiety with the requisite acid chloride (Lv═Cl), mixedanhydride (e.g., Lv═diphenyl phosphoryl,bis(2-oxo-3-oxazolidinyl)phosphinyl, or acyloxy of the general formulaof O—C(O)—R_(Lv), where R_(Lv) includes phenyl or t-butyl), orcarboxylic acid (Lv═OH) in the presence of an activating agent. Suitableactivating reagents are well known in the art, for examples see Kiso,Y., Yajima, H. “Peptides” pp. 39-91, San Diego, Calif., Academic Press,(1995), and include, but are not limited to, agents such ascarbodiimides, phosphonium and uronium salts (such as HATU).

Generally, the acid is activated using HATU or is converted to the acylazide by using DPPA. The appropriate amine is added to a solution of theappropriate anhydride or azide to give the desired final compounds, butif the amine is in the form of an acid salt, it is first reacted withTEA before adding to the anhydride or azide. In some cases, the ester(Lv being OMe or OEt) may be reacted directly with the amine in analcoholic solvent heated to reflux temperature to give the compounds ofFormula I.

It will be apparent to those skilled in the art that the requisitecarboxylic acids can be obtained commercially or can be synthesized byknown procedures. The acid required in Example 1 is synthesized byacetylation of the corresponding phenol with acetylchloride. The acidsin Examples 2, 8-16 are synthesized from the corresponding esters byhydrolysis. Typical hydrolysis procedures are well known in the art.Preferably, the ester is treated with aqueous lithium hydroxide in asolvent such as dioxane. The requisite esters are synthesized from thereaction of a phenol and arylboronic acid as described in Tet. Lett.,2937-2940 (1998). The phenol and boronic acid are reacted in thepresence of a copper salt like copper (II) acetate and a base like TEA(Scheme 2). The acids for Examples 3-7 are commercially available. Theacids required for Examples 17-22 are synthesized from the correspondingesters by hydrolysis as described above. The esters are synthesized bythe reaction of a thiophenol with an aryl halide as described inSynlett, 1579-1581 (1999). Namely, the thiophenol and aryl iodide areheated in the presence of a palladium (0) source such astetrakis(triphenylphosphine)palladium (0) and a base, preferably sodiumtert-butoxide.

There are a variety of methods for constructing thioamides. One cantreat the corresponding amide with a reagent such as Lawesson's reagent(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide)(see Lawesson et. al. in Bull. Soc. Chim. Belg., 229 (1978)), or P₄S₁₀(see Chem. Rev., 45 (1961)). Alternatively one can use adithiocarboxylic ester to form a thioamide from the corresponding amide.

N-(2-azabicyclo[2.2.1]hept)-5-amine and 6-amine

where Lv can be —CH₂Ph, —CH(Me)Ph, —OH, —OMe, or —OCH₂Ph.

The respective amine precursors for Azabicyclo III and Azabicyclo IV canbe prepared by reduction of an oxime or an imine of the correspondingN-2-azabicyclo[2.2.1]-heptanone by methods known to one skilled in theart (see J. Labelled Compds. Radiopharm., 53-60 (1995), J. Med. Chem.988-995, (1998), Synth. Commun. 1895-1911 (1992), Synth. Commun.2009-2015 (1996)). The oximes can be prepared by treatment of theN-2-azabicyclo[2.2.1]heptanones with hydroxylamine hydrochloride in thepresence of a base. The imines can be prepared by treatment of theN-2-azabicyclo[2.2.1]-heptanones with a primary amine under dehydratingconditions. The N-2-azabicyclo[2.2.1]heptanones can be prepared by knownprocedures (see Tet. Lett. 1419-1422 (1999), J. Med. Chem. 2184-2191(1992), J. Med. Chem. 706-720 (2000), J. Org. Chem., 4602-4616 (1995)).

One of ordinary skill in the art will recognize that the methodsdescribed for the reaction of the unsubstituted3-amino-1-azabicyclo[2.2.1]heptane (R₂=H) are equally applicable tosubstituted compounds (R₂≠H). For where Azabicyclo I has substitution atC-2, compounds can be prepared from appropriately substituted nitroalcohols using procedures described in Tetrahedron (1997), 53, p. 11121as shown below. Methods to synthesize nitro alcohols are well known inthe art (see J. Am. Chem. Soc. (1947), 69, p 2608). The scheme below isa modification of the synthesis ofexo-3-amino-1-azabicyclo[2.2.1]heptane as the bis(hydropara-toluenesulfonate) salt, described in detail herein, to show how toobtain these amine precursors. The desired salt can be made usingstandard procedures.

For Azabicyclo II where R₂ is present at the C-6 position, compounds canalso be prepared by modification of intermediates described in thesynthesis of exo-3-amino-1-azabicyclo[2.2.1]heptane as the bis(hydropara-toluenesulfonate) salt, described in detail herein. For example,Int 6 can be oxidized to the aldehyde and treated with an organometallicreagent to provide Int 20 using procedures described in Tetrahedron(1999), 55, p 13899. Int 20 can be converted into the amine usingmethods described for the synthesis ofexo-3-amino-1-azabicyclo[2.2.1]heptane as the bis(hydropara-toluenesulfonate) salt. Once the amine is obtained, the desiredsalt can be made using standard procedures.

The schemes used are for making exo-3-amino-1-azabicyclo[2.2.1]heptane.However, the modifications discussed are applicable to make the endoisomer also.

There are several methods by which the amine precursor for Azabicyclo Ican be obtained.

The oximes can be prepared by treatment of the 3-quinuclidinones withhydroxylamine hydrochloride in the presence of base. The imines can beprepared by treatment of the 3-quinuclidinones with a primary amineunder dehydrating conditions. The 3-hydroxyquinuclidines can be preparedby reduction of the 3-quinuclidinones. The6-substituted-3-quinuclidinones can be prepared by known procedures (seeJ. Gen. Chem. Russia 3791-3795, (1963), J. Chem. Soc. Perkin Trans. I409-420 (1991), J. Org. Chem. 3982-3996 (2000)).

Amines

Preparation of the 1-azabicyclo-2.2.1 Amines

Synthesis of (3R,4S)-3-amino-1-azabicyclo[2.2.1]heptane as the bis(hydropara-toluenesulfonate) salt (exo-[2.2.1]-Amine):

Step A. Preparation of 2-(benzoyloxy)-1-nitroethane (Int 1).

Benzoyl chloride (14.9 mL, 128 mmol) is added to a stirred solution ofnitroethanol (9.2 mL, 128 mmol) in dry benzene (120 mL). The solution isrefluxed for 24 hr and then concentrated in vacuo. The crude product ispurified by flash chromatography on silica gel. Elution withhexanes-EtOAc (80:20) affords Int 1 as a white solid (68% yield): ¹H NMR(300 MHz, CDCl₃) δ 8.0, 7.6, 7.4, 4.9, 4.8.

Step B. Preparation of Ethyl E-4-(benzylamino)-2-butenoate (Int 2).

Ethyl E-4-bromo-2-butenoate (10 mL, 56 mmol, tech grade) is added to astirred solution of benzylamine (16 mL, 146 mmol) in CH₂Cl₂ (200 mL) atrt. The reaction mixture stirs for 15 min, and is diluted with ether (1L). The mixture is washed with saturated aqueous NaHCO₃ solution (3×)and water, dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue is purified by flash chromatography on silica gel. Elution withhexanes-EtOAc (70:30) affords Int 2 as a clear oil (62% yield): ¹H NMR(300 MHz, CDCl₃) δ 7.4-7.2, 7.0, 6.0, 4.2, 3.8, 3.4, 2.1-1.8, 1.3.

Step C. Preparation oftrans-4-nitro-1-(phenylmethyl)-3-pyrrolidineacetic acid ethyl ester (Int3).

A solution of Int 1 (6.81 g, 34.9 mmol) and Int 2 (7.65 g, 34.9 mmol) inEtOH (70 mL) stirs at rt for 15 h and is then concentrated in vacuo. Theresidue is diluted with ether (100 mL) and saturated aqueous NaHCO₃solution (100 mL). The organic layer is separated and dried over Na₂SO₄,filtered and concentrated in vacuo. The crude product is purified byflash chromatography on silica gel. Elution with hexanes-EtOAc (85:15)affords Int 3 as a clear oil (76% yield): ¹H NMR (300 MHz, CDCl₃) δ7.4-7.3, 4.8-4.7, 4.1, 3.8-3.6, 3.3-3.0, 2.7-2.6, 2.4-2.3, 1.2.

Step D. Preparation oftrans-4-amino-1-(phenylmethyl)-3-pyrrolidineacetic acid ethyl ester (Int4).

A mixture of Int 3 (3.28 g, 11.2 mmol) and RaNi (1.5 g) in EtOH (100 mL)is placed in a Parr bottle and hydrogenated for 4 h under an atmosphereof hydrogen (46 psi) at rt. The mixture is filtered through a pad ofCelite, and the solvent is removed in vacuo to afford Int 4 as a clearoil (100% yield): ¹H NMR (300 MHz, CDCl₃) δ 7.3-7.2, 4.1, 3.6, 3.2,3.0-2.9, 2.8, 2.8-2.6, 2.6-2.4, 2.30-2.2, 1.2.

Step E. Preparation oftrans-4-(1,1-dimethylethoxycarbonylamido)-1-(phenylmethyl)-3-pyrrolidineaceticacid ethyl ester (Int 5).

Di-tert-butyldicarbonate (3.67 g, 16.8 mmol) is added to a stirredsolution of Int 4 (2.94 g, 11.2 mmol) in CH₂Cl₂ (30 mL) cooled in an icebath. The reaction is allowed to warm to rt and stirred overnight. Themixture is concentrated in vacuo. The crude product is purified by flashchromatography on silica gel. Elution with hexanes-EtOAc (80:20) affordsInt 5 as a white solid (77% yield): ¹H NMR (300 MHz, CDCl₃) δ 7.4-7.2,5.1-4.9, 4.1, 4.0-3.8, 3.6, 3.2-3.0, 2.8-2.6, 2.5-2.4, 2.3-2.1, 1.4,1.3.

Step F. Preparation oftrans(tert-butoxycarbonylamino)-4-(2-hydroxyethyl)-1-(N-phenylmethyl)pyrrolidine(Int 6).

LiAlH₄ powder (627 mg, 16.5 mmol) is added in small portions to astirred solution of Int 5 (3.0 g, 8.3 mmol) in anhydrous THF (125 mL) ina −5° C. bath. The mixture is stirred for 20 min in a −5° C. bath, thenquenched by the sequential addition of water (0.6 mL), 15% (w/v) aqueousNaOH (0.6 mL) and water (1.8 mL). Excess anhydrous K₂CO₃ is added, andthe mixture is stirred for 1 h, then filtered. The filtrate isconcentrated in vacuo. The residue is purified by flash chromatographyon silica gel. Elution with EtOAc affords Int 6 as a white solid (94%yield): ¹H NMR (300 MHz, CDCl₃) δ 7.4-7.3, 5.3-5.2, 4.1-4.0, 3.9-3.7,3.3-3.2, 2.8-2.7, 2.3-2.1, 1.7, 1.5.

Int 6 is a racemic mixture that can be resolved via chromatography usinga Diacel chiral pack AD column. From the two enantiomers thus obtained,the (+)-enantiomer, [α]²⁵ _(D)+35 (c 1.0, MeOH), gives rise to thecorresponding enantiomerically pure exo-4-S final compounds, whereas the(−)-enantiomer, [α]²⁵ _(D)−34 (c 0.98, MeOH), gives rise toenantiomerically pure exo-4-R final compounds. The methods describedherein use the (+)-enantiomer of Int 6 to obtain the enantiomericallypure exo-4-S final compounds. However, the methods used are equallyapplicable to the (−)-enantiomer of Int 6, making non-critical changesto the methods provided herein to obtain the enantiomerically pureexo-4-R final compounds.

Step G. Preparation of exo3-(tert-butoxycarbonylamino)-1-azabicyclo[2.2.1]heptane (Int 7).

TEA (8.0 g, 78.9 mml) is added to a stirred solution of Int 6 (2.5 g,7.8 mmol) in CH₂Cl₂ (50 mL), and the reaction is cooled in an ice-waterbath. CH₃SO₂Cl (5.5 g, 47.8 mmol) is then added dropwise, and themixture is stirred for 10 min in an ice-water bath. The resulting yellowmixture is diluted with saturated aqueous NaHCO₃ solution, extractedwith CH₂Cl₂ several times until no product remains in the aqueous layerby TLC. The organic layers are combined, washed with brine, dried overNa₂SO₄ and concentrated in vacuo. The residue is dissolved in EtOH (85mL) and is heated to reflux for 16 h. The reaction mixture is allowed tocool to rt, transferred to a Parr bottle and treated with 10% Pd/Ccatalyst (1.25 g). The bottle is placed under an atmosphere of hydrogen(53 psi) for 16 h. The mixture is filtered through Celite, and freshcatalyst (10% Pd/C, 1.25 g) is added. Hydrogenolysis continuesovernight. The process is repeated three more times until thehydrogenolysis is complete. The final mixture is filtered through Celiteand concentrated in vacuo. The residue is purified by flashchromatography on silica gel. Elution with CHCl₃—MeOH—NH₄OH (90:9.5:0.5)affords Int 7 as a white solid (46% yield): ¹H NMR (300 MHz, CDCl₃) δ5.6-5.5, 3.8-3.7, 3.3-3.2, 2.8-2.7, 2.0-1.8, 1.7-1.5, 1.5.

Step H. Preparation of exo-3-amino-1-azabicyclo[2.2.1]heptanebis(hydro-para-toluenesulfonate).

Para-toluenesulfonic acid monohydrate (1.46 g, 7.68 mmol) is added to astirred solution of Int 7 (770 mg, 3.63 mmol) in EtOH (50 mL). Thereaction mixture is heated to reflux for 10 h, followed by cooling tort. The precipitate is collected by vacuum filtration and washed withcold EtOH to give exo-[2.2.1]-Amine as a white solid (84% yield): ¹H NMR(400 MHz, CD₃OD) δ 7.7, 7.3, 3.9-3.7, 3.7-3.3, 3.2, 2.4, 2.3-2.2,1.9-1.8.

Synthesis of endo-3-amino-1-azabicyclo[2.2.1]heptane as the bis(hydropara-toluenesulfonate) salt (endo-[2.2.1]-Amine)

Step I. Preparation of ethyl5-hydroxy-6-oxo-1,2,3,6-tetrahydropyridine-4-carboxylate (Int 10).

Absolute EtOH (92.0 mL, 1.58 mol) is added to a mechanically stirredsuspension of potassium ethoxide (33.2 g, 395 mmol) in dry toluene(0.470 L). When the mixture is homogeneous, 2-pyrrolidinone (33.6 g, 395mmol) is added, and then a solution of diethyl oxalate (53.1 mL, 390mmol) in toluene (98 mL) is added via an addition funnel. After completeaddition, toluene (118 mL) and EtOH (78 mL) are added sequentially. Themixture is heated to reflux for 18 h. The mixture is cooled to rt andaqueous HCl (150 mL of a 6.0 M solution) is added. The mixture ismechanically stirred for 15 min. The aqueous layer is extracted withCH₂Cl₂, and the combined organic layers are dried (MgSO₄), filtered andconcentrated in vacuo to a yellow residue. The residue is recrystallizedfrom EtOAc to afford Int 10 as a yellow solid (38% yield): ¹H NMR (300MHz, CDCl₃) δ 11.4, 7.4, 4.3, 3.4, 2.6, 1.3.

Step J. Preparation of ethyl cis-3-hydroxy-2-oxopiperidine-4-carboxylate(Int 11).

A mixture of Int 10 (15 g, 81 mmol) and 5% rhodium on carbon (2.0 g) inglacial acetic acid is placed under an atmosphere of hydrogen (52 psi).The mixture is shaken for 72 h. The mixture is filtered through Celite,and the filtrate is concentrated in vacuo to afford Int 11 as a whitesolid (98% yield): ¹H NMR (300 MHz, CDCl₃) δ 6.3, 4.2, 4.0-3.8, 3.4,3.3-3.2, 2.2, 1.3.

Step K. Preparation of cis-4-(hydroxymethyl)piperidin-3-ol (Int 12).

Int 11 (3.7 g, 19.9 mmol) as a solid is added in small portions to astirred solution of LiAlH₄ in THF (80 mL of a 1.0 M solution) in anice-water bath. The mixture is warmed to rt, and then the reaction isheated to reflux for 48 h. The mixture is cooled in an ice-water bathbefore water (3.0 mL, 170 mmol) is added dropwise, followed by thesequential addition of NaOH (3.0 mL of a 15% (w/v) solution) and water(9.0 mL, 500 mmol). Excess K₂CO₃ is added, and the mixture is stirredvigorously for 15 min. The mixture is filtered, and the filtrate isconcentrated in vacuo to afford Int 12 as a yellow powder (70% yield):¹H NMR (300 MHz, DMSO-d₆) δ 4.3, 4.1, 3.7, 3.5-3.2, 2.9-2.7, 2.5-2.3,1.5, 1.3.

Step L. Preparation of benzylcis-3-hydroxy-4-(hydroxymethyl)piperidine-1-carboxylate (Int 13).

N-(benzyloxy carbonyloxy)succinimide (3.04 g, 12.2 mmol) is added to astirred solution of Int 12 (1.6 g, 12.2 mmol) in saturated aqueousNaHCO₃ (15 mL) at rt. The mixture is stirred at rt for 18 h. The organicand aqueous layers are separated. The aqueous layer is extracted withether (3×). The combined organic layers are dried over anhydrous K₂CO₃,filtered and concentrated in vacuo to afford Int 13 as a yellow oil (99%yield): ¹H NMR (300 MHz, CDCl₃) δ 7.4-7.3, 5.2, 4.3, 4.1, 3.8-3.7,3.0-2.8, 2.1, 1.9-1.7, 1.4.

Step M. Preparation of benzyl cis-3-hydroxy-4-[(4-methylphenyl)sulfonyloxymethyl]piperidine-1-carboxylate (Int 14).

Para-toluenesulfonyl chloride (1.0 g, 5.3 mmol) is added to a stirredsolution of Int 13 (3.6 g, 5.3 mmol) in pyridine (10 mL) in a −15° C.bath. The mixture is stirred for 4 h, followed by addition of HCl (4.5mL of a 6.0 M solution). CH₂Cl₂ (5 mL) is added. The organic and aqueouslayers are separated. The aqueous layer is extracted with CH₂Cl₂. Thecombined organic layers are washed with brine, dried (MgSO₄), filteredand concentrated in vacuo to afford Int 14 as a colorless oil (78%yield): ¹H NMR (300 MHz, CDCl₃) δ 7.8, 7.4-7.2, 5.1, 4.3-4.2, 4.1,3.9-3.8, 2.9-2.7, 2.4, 1.9, 1.6-1.3.

Step N. Preparation of exo-1-azabicyclo[2.2.1]heptan-3-ol (Int 15).

A mixture of Int 14 (3.6 g, 8.6 mmol) and 10% Pd/C catalyst (500 mg) inEtOH (50 mL) is placed under an atmosphere of hydrogen. The mixture isshaken for 16 h. The mixture is filtered through Celite. Solid NaHCO₃(1.1 g, 13 mmol) is added to the filtrate, and the mixture is heated inan oil bath at 50° C. for 5 h. The solvent is removed in vacuo. Theresidue is dissolved in saturated aqueous K₂CO₃ solution. Continuousextraction of the aqueous layer using a liquid-liquid extractionapparatus (18 h), followed by drying the organic layer over anhydrousK₂CO₃ and removal of the solvent in vacuo affords Int 15 as a whitesolid (91% yield): ¹H NMR (300 MHz, CDCl₃) δ 3.8, 3.0-2.8, 2.6-2.5,2.4-2.3, 1.7, 1.1.

Step O. Preparation of endo-3-azido-1-azabicyclo[2.2.1]heptane (Int 16).

To a mixture of Int 15 (1.0 g, 8.9 mmol) and triphenyl phosphine (3.0 g,11.5 mmol) in toluene-THF (50 mL, 3:2) in an ice-water bath are addedsequentially a solution of hydrazoic acid in toluene (15 mL of ca. 2 Msolution) and a solution of diethyl azadicarboxylate (1.8 mL, 11.5 mmol)in toluene (20 mL). The mixture is allowed to warm to rt and stir for 18h. The mixture is extracted with aqueous 1.0M HCl solution. The aqueouslayer is extracted with EtOAc, and the combined organic layers arediscarded. The pH of the aqueous layer is adjusted to 9 with 50% aqueousNaOH solution. The aqueous layer is extracted with CH₂Cl₂ (3×), and thecombined organic layers are washed with brine, dried over Na₂SO₄,filtered and concentrated in vacuo. The crude product is purified byflash chromatography on silica gel. Elution with CHCl₃—MeOH—NH₄OH(92:7:1) affords Int 16 as a colorless oil (41% yield): ¹H NMR (300 MHz,CDCl₃) δ 4.1, 3.2, 2.8, 2.7-2.5, 2.2, 1.9, 1.5.

Step P. Preparation of endo-3-amino-1-azabicyclo[2.2.1]heptanebis(hydro-para-toluenesulfonate).

A mixture of Int 16 (250 mg, 1.8 mmol) and 10% Pd/C catalyst (12 mg) inEtOH (10 mL) is placed under an atmosphere of hydrogen (15 psi). Themixture is stirred for 1 h at rt. The mixture is filtered throughCelite, and the filtrate is concentrated in vacuo. The residue isdissolved in EtOH (10 mL) and para-toluenesulfonic acid monohydrate (690mg, 3.7 mmol) is added. The mixture is stirred for 30 min, and theprecipitate is filtered. The precipitate is washed sequentially withcold EtOH and ether. The precipitate is dried in vacuo to affordendo-[2.2.1]-Amine as a white solid (85% yield): ¹H NMR (300 MHz, CD₃OD)δ 7.7, 7.3, 4.2, 3.9, 3.6-3.4, 3.3-3.2, 2.4, 2.3, 2.1.

Preparation of 1-azabicyclo[3.2.1]octan-3-amine

Preparation of the 3R,5R-[3.2.1]-Amine

(3S)-1-[(S)-1-Phenethyl]-5-oxo-3-pyrrolidine-carboxylic acid

According to the literature procedure (Nielsen et al. J. Med. Chem 1990,70-77), a mixture of itaconic acid (123.17 g, 946.7 mmol) and(S)-(−)-α-methyl benzylamine (122.0 mL, 946.4 mmol) were heated (neat)in a 160° C. oil bath for 4 h. Upon cooling, MeOH (˜200 mL) was addedand the resulting solid collected by filtration. The solid was treatedwith EtOH (˜700 mL) and warmed using a steam bath until ˜450 mL solventremained. After cooling to rt, the solid was collected and dried toafford 83.2 g as a white crystalline solid: [α]²⁵ _(D)=−80 (c 0.97,DMSO). MS (EI) m/z 233 (M⁺), 233, 218, 160, 105, 104, 103, 91, 79, 78,77.

The lack of a resonance 3.59 indicates a single diastereomer. The otherdiastereomer can be retrieved from the initial MeOH triturant. Attemptsto crystallize this material generally led to small quantities of(3RS)-1-[(S)-1-phenethyl]-5-oxo-3-pyrrolidine-carboxylic acid.(3S)-1-[(S)-1-Phenethyl]-3-(hydroxymethyl)pyrrolidine

A suspension (3S)-1-[(S)-1-phenethyl]-5-oxo-3-pyrrolidine-carboxylicacid (82.30 g, 352.8 mmol) in Et₂O (200 mL) was added in small portionsto a slurry of LiAlH₄ (17.41 g, 458.6 mmol) in Et₂O (700 mL). Themixture began to reflux during the addition. The addition funnelcontaining the suspension was rinsed with Et₂O (2×50 mL), and themixture was heated in a 50° C. oil bath for an additional 2 h and firstallowed to cool to rt and then further cooled using an ice bath. Themixture was carefully treated with H₂O (62 mL). The resultingprecipitate was filtered, rinsed with Et₂O, and discarded. The filtratewas concentrated to a yellow oil. When EtOAc was added to the oil, asolid began to form. Hexane was then added and removed by filtration anddried to afford 43.3 g as a white solid. [α]²⁵ _(D)=−71 (c 0.94, CHCl₃).MS (EI) m/z 205 (M⁺), 191, 190, 128, 105, 91, 86, 84, 79, 77, 51.(3R)-1-[(S)-1-Phenethyl]-3-(cyanomethyl)pyrrolidine

A solution of (3S)-1-[(S)-1-phenethyl]-3-(hydroxymethyl)pyrrolidine(42.75 g, 208.23 mmol) in chloroform (350 mL) was heated to reflux underN₂. The solution was treated with a solution of thionyl chloride (41.8mL, 573 mmol) in chloroform (40 mL) dropwise over 45 min. The mixturestirred for an additional 30 min, was cooled and concentrated. Theresidue was diluted with H₂O (˜200 mL), 1 N NaOH was added until a pH ˜8(pH paper). A small portion (˜50 mL) of sat. NaHCO₃ was added and thebasic mixture was extracted with EtOAc (3×400 mL), washed with brine,dried (MgSO₄), filtered and concentrated to give 46.51 g of a red-orangeoil for (3S)-1-[(S)-1-phenethyl]-3-(chloromethyl)pyrrolidine: R_(ƒ:)0.50 (EtOAc-hexane 1:1); MS (ESI+) m/z 224.2 (MH⁺). The chloride (46.35g, 208.0 mmol) was transferred to a flask, dimethyl sulfoxide (200 mL)was added, and the solution was treated with NaCN (17.84 g, 363.9 mmol).The mixture was heated under N₂ in a 100° C. oil bath overnight and wascooled. The brown mixture was poured into H₂O (300 mL) and extractedwith EtOAc (1000 mL in portions). The combined organic layer was washedwith H₂O (6×˜50 mL), brine (˜100 mL), dried (MgSO₄), filtered andconcentrated to give 40.61 g as an orange-red oil: R_(ƒ:) 0.40(EtOAc-PhCH₃ 1:1). MS (ESI+) for m/z 215.2 (M+H⁺).(3R)-Methyl 1-[(S)-1-phenylethyl]pyrrolidine-3-acetate

Acetyl chloride (270 mL, 3.8 mol) was carefully added to a flaskcontaining chilled (0° C.) methanol (1100 mL). After the addition wascomplete, the acidic solution stirred for 45 min (0° C.) and then(3R)-1-[(S)-1-phenethyl]-3-(cyanomethyl)pyrrolidine (40.50 g, 189.0mmol) in methanol (200 mL) was added. The ice bath was removed and themixture stirred for 100 h at rt. The resulting suspension wasconcentrated. Water (˜600 mL) was added, the mixture stirred for 45 minand then the pH was adjusted (made basic) through the addition of ˜700mL sat. aq. NaHCO₃. The mixture was extracted with EtOAc (3×300 mL). Thecombined organics were washed with brine, dried (MgSO₄), filteredthrough celite and concentrated to give 36.86 g as an orange-red oil. MS(ESI+) m/z 248.2 (M+H⁺).(5R)-1-Azabicyclo[3.2.1]octan-3-one hydrochloride

A solution of (3R)-methyl 1-[(S)-1-phenylethyl]pyrrolidine-3-acetate(25.72 g, 104.0 mmol) in THF (265 mL) was cooled under N₂ in aCO₂/acetone bath. Next, ICH₂Cl (22.7 mL, 312.0 mmol) was added, and themixture stirred for 30 min. A solution of 2.0M lithium diisopropylamide(heptane/THF/ethylbenzene, 156 mL, 312 mmol) was added slowly over 30min. The internal temperature reached a maximum of −40° C. during thisaddition. After 1 h, sat. NH₄Cl (100 mL) was added and the mixture wasallowed to warm to rt. The organic layer was separated, dried (MgSO₄),filtered and concentrated. The resulting red-brown foam waschromatographed (300 g SiO₂, CHCl₃—MeOH—NH₄OH (89:10:1) followed byCHCl₃—MeOH (3:1). The product fractions were pooled and concentrated toafford (5R)-3-oxo-1-[(1S)-1-phenylethyl]-1-azoniabicyclo[3.2.1]octanechloride (10.12 g) as a tan foam (MS (ESI+) m/z 230.1 (M+H⁺). This foam(10.1 g, 38 mmol) was taken up in MeOH (500 mL), 10% Pd(C) (3.0 g) addedand the mixture was hydrogenated (45 psi) overnight. The mixture wasfiltered and re-subjected to the reduction conditions (9.1 g, 10% Pd/C,50 psi). After 5 h, TLC indicated the consumption of the(5R)-3-oxo-1-[(1S)-1-phenylethyl]-1-azoniabicyclo[3.2.1]octane chloride.The mixture was filtered, concentrated and triturated (minimal iPrOH) togive 3.73 g of (5R)-1-azabicyclo[3.2.1]octan-3-one hydrochloride, in twocrops, as an off-white solid: [α]²⁵ _(D)=33 (c 0.97, DMSO). MS (EI) m/z125 (M⁺).(3R,5R)-1-azabicyclo[3.2.1]octan-3-amine dihydrochloride

To a flask containing (5R)-1-azabicyclo[3.2.1]octan-3-one hydrochloride(3.64 g, 22.6 mmol), hydroxylamine hydrochloride (2.04 g, 29.4 mmol),and ethanol (130 mL) was added sodium acetate trihydrate (9.23 g, 67.8mmol). The mixture stirred for 3 h and was filtered and concentrated.The resulting white solid was taken up in n-propanol (100 mL) and sodium(˜13.6 g, 618 mmol) was added over 20-25 portions. The reactionspontaneously began to reflux, and the reaction was heated in an oilbath (100° C.). The addition was complete in ˜20 min and the mixture hadsolidified after ˜40 min. The oil bath was removed and n-propanol (2×25mL) was added dissolving the remaining sodium metal. The mixture wascarefully quenched through the dropwise addition of H₂O (100 mL).Saturated aq. NaCl (20 mL) was added, and the layers were separated. Theorganic layer was dried (MgSO₄), filtered, treated with freshly preparedMeOH/HCl, and concentrated. The resulting solid was triturated with 30mL EtOH, filtered and dried in vaccuo to afford 3.51 g as a white solid:[α]²⁵ _(D)=−3 (c 0.94, DMSO). MS (FAB) m/z 127 (MH⁺).

Preparation of endo-1-azabicyclo[3.2.1]octan-3-amine dihydrochloride(endo-[3.2.1]-Amine)

A mixture of 1-azabicyclo[3.2.1]octan-3-one hydrochloride (2.80 g, 17.3mmol), ethanol (25 mL), and hydroxylamine hydrochloride (1.56 g, 22.4mmol) is treated with sodium acetate trihydrate (7.07 g, 51.2 mmol). Themixture is stirred for 3 h and evaporated in vacuo. The residue isdiluted with CH₂Cl₂, treated with charcoal, filtered and evaporated. Theresulting oxime (3.1 mmol) is treated with acetic acid (30 mL) andhydrogenated at 50 psi over PtO₂ (50 mg) for 12 h. The mixture is thenfiltered and evaporated. The residue is taken up in a minimal amount ofwater (6 mL) and the pH is adjusted to >12 using solid NaOH. The mixtureis then extracted with ethyl acetate (4×25 mL), dried (MgSO₄), filtered,treated with ethereal HCl, and evaporated to give the giveendo-[3.2.1]-Amine.

Preparation of the 3.2.2 Amines

Preparation of tert-butyl 4-(2-oxopropylidene)piperidine-1-carboxylate(Int 101):

Sodium hydride (60% oil dispersion, 2.01 g, 50.2 mmol) is washed withpentane (3×) and suspended in dry THF (40 mL). The solution is cooled to0° C. before diethyl(2-oxopropyl)phosphonate (9.75 g, 50.2 mmol) isadded dropwise. After complete addition, the solution is warmed to rtand stirred for 30 min. tert-Butyl 4-oxo-1-piperidinecarboxylate (5.0 g,25.1 mmol) is added in portions over 10 min, followed by stirring at rtfor 2 h. A saturated aqueous solution of ammonium chloride is added,followed by dilution with ether. The organic layer is extracted withwater. The organic layer is dried over anhydrous MgSO₄, filtered andconcentrated to a yellow oil. The crude product is purified by flashchromatography on silica gel. Elution with hexanes-ether (60:40) gave4.5 g (75%) of Int 101 as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 6.2,3.5, 3.4, 2.9, 2.3, 2.2, 1.5.

Preparation of tert-butyl 4-(2-oxopropyl)piperidine-1-carboxylate (Int102):

A mixture of Int 101 (4.5 g, 19 mmol) and 10% palladium on activatedcarbon (450 mg) in EtOH (150 mL) is placed in a Parr bottle andhydrogenated for 5 h at 50 psi. The mixture is filtered through Celite,and the filtrate is concentrated in vacuo to afford 4.3 g (94%) of Int102 as a clear oil: ¹H NMR (400 MHz, CDCl₃) δ 4.1, 2.8, 2.4, 2.2, 2.0,1.7, 1.5, 1.1.

Preparation of tert-butyl4-(3-bromo-2-oxopropyl)piperidine-1-carboxylate (Int 103):

To a stirred solution lithium hexamethyldisilylamide in THF (20.0 mL,1.0 M) in a −78° C. bath is added chlorotrimethylsilane (11.0 mL, 86.4mmol) dropwise. The mixture is stirred at −78° C. for 20 min, followedby addition of Int 102 (3.21 g, 13.3 mmol) in a solution of THF (50 mL)dropwise. After complete addition, the mixture is stirred at −78° C. for30 min. The mixture is warmed to 0° C. in an ice-water bath andphenyltrimethylammonium tribromide (5.25 g, 14.0 mmol) is added. Themixture is stirred in an ice-bath for 30 min, followed by the additionof water and ether. The aqueous layer is washed with ether, and thecombined organic layers are washed with saturated aqueous sodiumthiosulfate solution. The organic layer is dried over anhydrous MgSO₄,filtered and concentrated in vacuo to afford a yellow oil. The crudeproduct is purified by flash chromatography on silica gel. Elution withhexanes-ether (60:40) gave 2.2 g (52%) of Int 103 as a lt. yellow oil:¹H NMR (400 MHz, CDCl₃) δ 4.2-4.1, 3.9, 2.8, 2.7, 2.6, 2.1-2.0, 1.7,1.5, 1.2-1.1.2.

Preparation of 1-bromo-3-piperidin-4-ylacetone trifluoroacetate (Int104):

To a stirred solution of Int 103 (2.2 g, 6.9 mmol) in CH₂Cl₂ (30 mL) inan ice-water bath is added trifluoroacetic acid (10 mL, 130 mmol). Themixture is stirred at 0° C. for 30 min. The volatiles are removed invacuo to afford 2.0 g (87%) of Int 104 as a yellow residue: MS (ESI) forC₈H₁₅BrNO [M+H] m/e 220.

Preparation of 1-azabicyclo[3.2.2]nonan-3-one (Int 105):

To a stirred solution of DIEA (13 mL) in acetoniltrile (680 mL) atreflux temperature is added a solution of Int 104 (2.0 g, 6.0 mmol) inacetonitrile (125 mL) over a 4 h period via syringe pump. The mixture iskept at reflux temperature overnight. The mixture is concentrated invacuo and the remaining residue is partitioned between a saturatedaqueous K₂CO₃ solution and CHCl₃—MeOH (90:10). The aqueous layer isextracted with CHCl₃—MeOH (90:10), and the combined organic layers aredried (MgSO₄), filtered and concentrated in vacuo to a brown oil. Thecrude product is purified by flash chromatography on silica gel. Elutionwith CHCl₃—MeOH—NH₄OH 95:4.5:0.5) gives 600 mg (72%) of Int 105 as aclear solid: ¹H NMR (400 MHz, CDCl₃) δ 3.7, 3.3-3.2, 3.1-3.0, 2.7, 2.3,2.0-1.8.

Preparation of 1-azabicyclo[3.2.2]nonan-3-aminebis(4-methylbenzenesulfonate) ([3.2.2]-Amine)

To a stirred mixture of Int 105 (330 mg, 2.4 mmol) and sodiumacetate.trihydrate (670 mg, 4.8 mmol) in EtOH (6.0 mL) is addedhydroxylamine.hydrochloride (200 mg, 2.8 mmol). The mixture is stirredat rt for 10 h. The mixture is filtered and the filtrate is concentratedin vacuo to a yellow solid. To a solution of the solid (350 mg, 2.3mmol) in n-propanol (30 mL) at reflux temperature is added sodium metal(2.0 g, 87 mmol) in small portions over 30 min. Heating at reflux iscontinued for 2 h. The solution is cooled to rt and brine is added. Themixture is extracted with n-propanol, and the combined organic layersare concentrated in vacuo. The residue is taken up in CHCl₃ and theremaining solids are filtered. The filtrate is dried over anhydrousMgSO₄, filtered and concentrated in vacuo to a clear solid. To a stirredsolution of the solid (320 mg, 2.3 mmol) in EtOH (4 mL) is addedp-toluenesulfonic acid monohydrate (875 mg, 4.6 mmol). The solution iswarmed in a water bath to 45° C. for 30 min, followed by concentrationof the solvent to afford 710 mg (62%) of [3.2.2]-Amine as a white solid:¹H NMR (400 MHz, CD₃OD) δ 7.7, 7.3, 4.1-3.9, 3.6-3.4, 2.6-2.5, 2.4,2.2-2.1, 2.1-2.0, 1.9.

Resolution of stereoisomers

The amine can be coupled to form the appropriate amides as a racemicmixture. The racemic mixture can then be resolved by chromatographyusing chiral columns or chiral HPLC, techniques widely known in the art,to provide the requisite resolved enantiomers 3(R) and 3(S) of saidamides.

Coupling

The examples provided are carried out using one amine. However, any ofthe amine isomers may be used making non-critical changes but startingwith the amine not identified. Thus, the stereospecificity of theresulting compound may not drawn. But, the scope of this inventionincludes the different stereoisomers as described herein as well asracemic mixtures.

EXAMPLE 1exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-hydroxyphenoxy)benzamide

Acetylchloride (1.5 mL, 21 mmol) is added to a solution of4-(4-hydroxyphenoxy)benzoic acid (2.3 g, 10 mmol) and TEA (2.9 mL, 21mmol) in CH₂Cl₂ (50 mL). The reaction is stirred for 16 hours at roomtemperature. The reaction mixture is diluted with CH₂Cl₂ and washedthree times with saturated NaHCO₃. The organic layer is dried (MgSO₄),filtered and concentrated in vacuo. The resulting material is dissolvedin dioxane (6 mL). Aqueous LiOH (1N, 930 μL) is added, and the reactionis allowed to stir for one hour at room temperature. The reactionmixture is poured into CH₂Cl₂ and washed twice with KHSO₄. The organiclayer is dried (MgSO₄), filtered and concentrated in vacuo to give4-(4-acetoxyphenoxy)benzoic acid (1.5 g, 87%). ¹H NMR (300 MHz, DMSO) δ12.80, 7.96, 7.23-7.13, 7.04, 2.29.

Coupling: 4-(4-Acetoxyphenoxy)benzoic acid can be coupled withexo-[2.2.1]-Amine using conditions described herein.

EXAMPLE 2exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-acetamidophenoxy)benzamide

Dry air is bubbled through a solution of 4-acetamidophenol (320 mg, 2.1mmol), copper(II) acetate (384 mg, 2.1 mmol), TEA (1.5 mL, 10.5 mol),(4-methoxycarbonylphenyl)boronic acid (760 mg, 4.2 mmol), and powderedmolecular sieves (2 g) in CH₂Cl₂ (21 mL) for 16 hours at roomtemperature. The resulting material is concentrated and purified byflash column chromatography (25-50% EtOAc in heptane) to give methyl4-(4-acetamidophenoxy)benzoate (450 mg, 75%). ¹H NMR (300 MHz, DMSO) δ8.01, 7.54, 7.27, 7.05, 6.98, 3.92, 2.22.

Aqueous LiOH (1M, 3.12 mL) is added to a suspension of methyl4-(4-acetamidophenoxy)benzoate (445 mg, 1.6 mmol) in dioxane (6 mL). Thereaction is stirred for 90 minutes at room temperature. Concentrated HCl(1.5 mL) is added to lower the pH to less than 6 and the resultingprecipitate is collected by filtration. The filter cake is washed withwater then dried to give 4-(4-acetamidophenoxy)benzoic acid (337 mg,80%). MS for C₁₅H₁₃NO₄ (ESI) (M−H)⁻ m/z 270.

Coupling: 4-(4-Acetamidophenoxy)benzoic acid can be coupled withexo-[2.2.1]-Amine using conditions described herein.

EXAMPLE 3 exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-phenoxybenzamide

4-Phenoxybenzoic acid can be coupled with exo-[2.2.1]-Amine usingconditions described herein.

The following compounds can be made from the coupling carboxylic acidswith exo-[2.2.1]-Amine using conditions described herein.

EXAMPLE 4 exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-benzylbenzamide(from 4-benylbenzoic acid) EXAMPLE 5exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(phenylsulfanyl)-benzamide,(from 4-(phenylsulfanyl)benzoic acid) EXAMPLE 6exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-phenoxybenzamide (from3-phenoxybenzoic acid) EXAMPLE 7exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-benzoylbenzamide (from4-benzoylbenzoic acid) EXAMPLE 8exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-fluorophenoxy)benzamide

To a flask with 4-fluorophenyl boronic acid (2.1 g, 15 mmol), copper(II)acetate (1.4 g, 7.5 mmol), activated powdered molecular sieves(approximately 2 g), and methyl 4-hydroxybenzoate (1.2 g, 7.5 mmol) isadded TEA (5.2 mL, 38 mmol) followed by CH₂Cl₂ (75 mL). The reaction isstirred for 16 hours at room temperature with air bubbling through it.The reaction mixture is diluted with CH₂Cl₂ and filtered through silicagel. The silica gel is washed with EtOAc-heptane. The solution isconcentrated in vacuo and dissolved in dioxane (15 mL). To this solutionis added aqueous LiOH (1N, 15 mL) and stirred for 18 hours at roomtemperature. To this reaction mixture is added aqueous HCl (1N) untilacidic, having a pH less than 6. The resulting precipitate is collectedby filtration and rinsed with water, and dried in vacuo to give4-(4-fluorophenoxy)benzoic acid (1.6 g, 90%). MS for C₁₃H₉FO₃ (ESI)(M−H)⁻ m/z 231.

Coupling 4-(4-Fluorophenoxy)benzoic acid can be coupled withexo-[2.2.1]-Amine using conditions described herein.

Example 9 can be made from coupling the boronic acid withexo-[2.2.1]-Amine using conditions described herein:

EXAMPLE 9exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(2-fluorophenoxy)-benzamide(from 2-fluorophenylboronic acid) EXAMPLE 10exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3-fluorophenoxy)-benzamide4-methylbenzenesulfonate (from 3-fluorophenylboronic acid)

To a stirred solution of 4-(3-fluorophenoxy)benzoic acid (116 mg, 0.5mmol) in anhydrous DMF (10 mL) are added DIEA (265 μL, 1.52 mmol) andexo-(4S)-[2.2.1]-Amine (228 mg, 0.5 mmol). The mixture is cooled to 0°C., and HATU (190 mg, 0.5 mmol) is added in one portion. The reactionmixture is allowed to warm to room temperature and stir overnight. Thesolvent is removed in vacuo and the residue is partitioned betweensaturated aqueous K₂CO₃ solution and chloroform. The aqueous layer isextracted with chloroform (2×). The combined organic layers are washedwith brine, dried (Na₂SO₄), filtered and concentrated in vacuo. Thecrude product is purified by flash chromatography on silica gel. Elutionwith chloroform-methanol-ammonium hydroxide (89:9:1) gives the productas a yellow solid (164 mg, 99%).

To a stirred solution of the above amide (164 mg, 0.50 mmol) in methanol(5 mL) is added a warm solution of para-toluenesulfonic acid monohydrate(95 mg, 0.50 mmol) in methanol (5 mL). The mixture is stirred for 10 minat 50° C. The solvent is removed in vacuo and the remaining residue isdiluted with acetone (5 mL). The mixture is stirred overnight at roomtemperature. The solid is collected by filtration, washed with acetone,and drying under high vacuum overnight gives 200 mg (77%) of the titlecompound as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 7.9, 7.7, 7.4, 7.2,7.1, 7.0-6.8, 4.2, 3.8, 3.5-3.3, 3.3-3.2, 3.1, 2.4, 2.2, 1.9.

The following examples can be made from coupling the boronic acids withexo-[2.2.1]-Amine using conditions described herein:

EXAMPLE 11exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(2-chlorophenoxy)-benzamide(from 2-chlorophenylboronic acid) EXAMPLE 12exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3-chlorophenoxy)-benzamide(from 3-chlorophenylboronic acid) EXAMPLE 13exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-chlorophenoxy)-benzamide(from 4-chlorophenylboronic acid) EXAMPLE 14exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(2-methoxyphenoxy)-benzamide(from 2-methoxyphenylboronic acid) EXAMPLE 15exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3-methoxyphenoxy)-benzamide(from 3-methoxyphenylboronic acid) EXAMPLE 16exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-methoxyphenoxy)-benzamide(from 4-methoxyphenylboronic acid) EXAMPLE 17exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3-chlorophenylsulfanyl)-benzamide

A flask containing 3-chlorothiophenol (0.29 mL, 2.5 mmol), potassiumtert-butoxide (0.28 g, 2.5 mmol), tetrakis(triphenylphosphine)palladium(0) (0.23 g, 0.2 mmol), and methyl 4-iodobenzoate (0.66 g, 2.5 mmol) isvacuum purged and N₂ filled three times. To this flask is added THF (50mL) and the mixture is stirred at reflux for 24 hours. The solution isdiluted with CH₂Cl₂ and extracted three times with 1N NaOH. The organiclayer is dried (MgSO₄) and concentrated in vacuo. The crude product ispurified by flash-column chromatography (gradient of 0-1% EtOAc inheptane) to give methyl 4-(3-chlorosulfanyl)benzoate (0.53 g, 90%). ¹HNMR (300 MHz, CDCl₃) δ 7.96, 7.44-7.43, 7.34-7.29, 3.92.

Methyl 4-(3-chlorosulfanyl)benzoate (0.53 g, 1.89 mmol) is dissolved indioxane (4 mL) followed by addition of aqueous LiOH (1M, 4 mL). Themixture is stirred at room temperature for 5 hours then acidified withaqueous 1N HCl to a pH of less than 6. The resulting precipitate iscollected by filtration, rinsed with water, and dried in vacuo to give4-(3-chlorosulfanyl)benzoic acid(0.44 g, 89%). MS for C₁₃H₉CIO₂S (ESI)(M−H)⁻ m/z 263.

Coupling 4-(3-Chlorosulfanyl)benzoic acid can be coupled withexo-[2.2.1]-Amine using conditions described herein.

The following compounds can be made by coupling the thiophenols withexo-[2.2.1]-Amine using conditions described herein.

EXAMPLE 18exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-chlorophenyl-sulfanyl)benzamide(from 4-chlorothiophenol) EXAMPLE 19exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(2-chlorophenyl-sulfanyl)benzamide(from 2-chlorothiophenol) EXAMPLE 20exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-methoxyphenyl-sulfanyl)benzamide(from 4-methoxythiophenol) EXAMPLE 21exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3-methoxyphenyl-sulfanyl)benzamide(from 3-methoxythiophenol) EXAMPLE 22exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(2-methoxyphenyl-sulfanyl)benzamide(from 2-methoxythiophenol)

The present invention also includes, by representation but notlimitation, any one or more or combintation of the following compoundsand pharmaceutically acceptable salts thereof, both of which can be madeby one of ordinary skill in the art using the procedures provided makingnon-critical changes:

-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-hydroxyphenoxy)benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-acetamidophenoxy)benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-phenoxybenzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-benzylbenzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(phenylsulfanyl)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-phenoxybenzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-fluorophenoxy)benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(2-fluorophenoxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-fluorophenoxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(2-chlorophenoxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-chlorophenoxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-chlorophenoxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(2-methoxyphenoxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-methoxyphenoxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-methoxyphenoxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-chlorophenylsulfanyl)benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-chlorophenyl-sulfanyl)benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(2-chlorophenyl-sulfanyl)benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-methoxyphenyl-sulfanyl)benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-methoxyphenyl-sulfanyl)benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(2-methoxyphenyl-sulfanyl)benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-aminophenoxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-aminophenoxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(2-aminophenoxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-acetylphenoxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-acetylphenoxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(2-acetylphenoxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-carbamoylphenoxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-carbamoylphenoxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(2-carbamoylphenoxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-cyanophenoxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-cyanophenoxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(2-cyanophenoxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(thiophen-2-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(5-methylthiophen-2-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(5-chlorothiophen-2-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(5-methoxythiophen-2-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(5-trifluoromethylthiophen-2-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-methylthiophen-2-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-chlorothiophen-2-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-methoxythiophen-2-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-trifluoromethylthiophen-2-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(furan-2-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(5-methylfuran-2-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(5-chlorofuran-2-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(5-methoxyfuran-2-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(5-trifluoromethylfuran-2-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-methylfuran-2-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-chlorofuran-2-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-methoxyfuran-2-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-trifluoromethylfuran-2-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(oxazol-2-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(oxazol-5-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(thiazol-2-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(thiazol-5-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-([1,3,4]oxadiazol-2-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-([1,3,4]thiadiazol-2-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-aminophenylsulfanyl)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-aminophenylsulfanyl)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(2-aminophenylsulfanyl)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-acetylphenylsulfanyl)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-acetylphenylsulfanyl)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(2-acetylphenylsulfanyl)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-carbamoylphenylsulfanyl)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-carbamoylphenylsulfanyl)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(2-carbamoylphenylsulfanyl)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-hydroxyphenylsulfanyl)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-hydroxyphenylsulfanyl)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(2-hydroxyphenylsulfanyl)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-acetamidophenylsulfanyl)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-acetamidophenylsulfanyl)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(2-acetamidophenylsulfanyl)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(thiophen-2-ylsulfanyl)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(5-methylthiophen-2-ylsulfanyl)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(5-chlorothiophen-2-ylsulfanyl)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(5-trifluoromethylthiophen-2-ylsulfanyl)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(furan-2-ylsulfanyl)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(5-methylfuran-2-ylsulfanyl)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(5-chlorofuran-2-ylsulfanyl)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(oxazol-2-ylsulfanyl)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(5-chlorooxazol-2-ylsulfanyl)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(5-methoxyoxazol-2-ylsulfanyl)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(5-trifluoromethyloxazol-2-ylsulfanyl)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(oxazol-2-ylsulfanyl)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(oxazol-5-ylsulfanyl)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(thiazol-2-ylsulfanyl)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(thiazol-5-ylsulfanyl)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-([1,3,4]oxadiazol-2-ylsulfanyl)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-([1,3,4]thiadiazol-2-ylsulfanyl)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(5-trifluoromethylpyrrol-2-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(3H-imidazol-4-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(isoxazol-2-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(isothiazol-2-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(pyrrol-2-ylsulfanyl)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(3H-imidazol-4-ylsulfanyl)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(isoxazol-2-ylsulfanyl)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(isothiazol-2-ylsulfanyl)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(6-methylpyridin-3-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(6-chloropyridin-3-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(6-methoxypyridin-3-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(6-trifluoromethylpyridin-3-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(2-chloropyridin-4-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(5-chloropyridin-2-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-chloropyridin-2-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(6-chloropyridin-2-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(5-chloropyridin-3-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(2-chloropyridin-3-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-chloropyridin-3-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-chloropyridin-4-yloxy)-benzamide;-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-chloropyridin-2-yloxy)-benzamide;    or-   N-[6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-4-(6-chloropyridin-3-ylsulfanyl)-benzamide.

The present invention also includes, by representation but notlimitation, any one or more or combintation of the following compoundsand pharmaceutically acceptable salts thereof, both of which can be madeby one of ordinary skill in the art using the procedures provided makingnon-critical changes:

-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-hydroxyphenoxy)benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-acetamidophenoxy)benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-phenoxybenzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-benzylbenzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(phenylsulfanyl)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-phenoxybenzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-fluorophenoxy)benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(2-fluorophenoxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3-fluorophenoxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(2-chlorophenoxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3-chlorophenoxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-chlorophenoxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(2-methoxyphenoxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3-methoxyphenoxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-methoxyphenoxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3-chlorophenylsulfanyl)benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-chlorophenyl-sulfanyl)benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(2-chlorophenyl-sulfanyl)benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-methoxyphenyl-sulfanyl)benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3-methoxyphenyl-sulfanyl)benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(2-methoxyphenyl-sulfanyl)benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-aminophenoxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3-aminophenoxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(2-aminophenoxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-acetylphenoxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3-acetylphenoxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(2-acetylphenoxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-carbamoylphenoxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3-carbamoylphenoxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(2-carbamoylphenoxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-cyanophenoxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3-cyanophenoxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(2-cyanophenoxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(thiophen-2-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(5-methylthiophen-2-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(5-chlorothiophen-2-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(5-methoxythiophen-2-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(5-trifluoromethylthiophen-2-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-methylthiophen-2-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-chlorothiophen-2-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-methoxythiophen-2-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-trifluoromethylthiophen-2-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(furan-2-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(5-methylfuran-2-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(5-chlorofuran-2-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(5-methoxyfuran-2-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(5-trifluoromethylfuran-2-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-methylfuran-2-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-chlorofuran-2-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-methoxyfuran-2-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-trifluoromethylfuran-2-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(oxazol-2-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(oxazol-5-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(thiazol-2-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(thiazol-5-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-([1,3,4]oxadiazol-2-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-([1,3,4]thiadiazol-2-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-aminophenylsulfanyl)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3-aminophenylsulfanyl)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(2-aminophenylsulfanyl)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-acetylphenylsulfanyl)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3-acetylphenylsulfanyl)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(2-acetylphenylsulfanyl)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-carbamoylphenylsulfanyl)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3-carbamoylphenylsulfanyl)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(2-carbamoylphenylsulfanyl)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-hydroxyphenylsulfanyl)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3-hydroxyphenylsulfanyl)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(2-hydroxyphenylsulfanyl)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-acetamidophenylsulfanyl)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3-acetamidophenylsulfanyl)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(2-acetamidophenylsulfanyl)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(thiophen-2-ylsulfanyl)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(5-methylthiophen-2-ylsulfanyl)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(5-chlorothiophen-2-ylsulfanyl)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(5-trifluoromethylthiophen-2-ylsulfanyl)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(furan-2-ylsulfanyl)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(5-methylfuran-2-ylsulfanyl)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(5-chlorofuran-2-ylsulfanyl)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(oxazol-2-ylsulfanyl)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(5-chlorooxazol-2-ylsulfanyl)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(5-methoxyoxazol-2-ylsulfanyl)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(5-trifluoromethyloxazol-2-ylsulfanyl)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(oxazol-2-ylsulfanyl)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(oxazol-5-ylsulfanyl)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(thiazol-2-ylsulfanyl)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(thiazol-5-ylsulfanyl)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-([1,3,4]oxadiazol-2-ylsulfanyl)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-([1,3,4]thiadiazol-2-ylsulfanyl)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(5-trifluoromethylpyrrol-2-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3H-imidazol-4-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(isoxazol-2-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(isothiazol-2-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(pyrrol-2-ylsulfanyl)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3H-imidazol-4-ylsulfanyl)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(isoxazol-2-ylsulfanyl)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(isothiazol-2-ylsulfanyl)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(6-methylpyridin-3-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(6-chloropyridin-3-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(6-methoxypyridin-3-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(6-trifluoromethylpyridin-3-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(2-chloropyridin-4-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(5-chloropyridin-2-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-chloropyridin-2-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(6-chloropyridin-2-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(5-chloropyridin-3-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(2-chloropyridin-3-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-chloropyridin-3-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3-chloropyridin-4-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3-chloropyridin-2-yloxy)-benzamide;-   exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(6-chloropyridin-3-ylsulfanyl)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-hydroxyphenoxy)benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-acetamidophenoxy)benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-phenoxybenzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-benzylbenzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(phenylsulfanyl)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-phenoxybenzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-fluorophenoxy)benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(2-fluorophenoxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(3-fluorophenoxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(2-chlorophenoxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(3-chlorophenoxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-chlorophenoxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(2-methoxyphenoxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(3-methoxyphenoxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-methoxyphenoxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(3-chlorophenylsulfanyl)benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-chlorophenyl-sulfanyl)benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(2-chlorophenyl-sulfanyl)benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-methoxyphenyl-sulfanyl)benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(3-methoxyphenyl-sulfanyl)benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(2-methoxyphenyl-sulfanyl)benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-aminophenoxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(3-aminophenoxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(2-aminophenoxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-acetylphenoxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(3-acetylphenoxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(2-acetylphenoxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-carbamoylphenoxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(3-carbamoylphenoxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(2-carbamoylphenoxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-cyanophenoxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(3-cyanophenoxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(2-cyanophenoxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(thiophen-2-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(5-methylthiophen-2-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(5-chlorothiophen-2-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(5-methoxythiophen-2-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(5-trifluoromethylthiophen-2-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-methylthiophen-2-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-chlorothiophen-2-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-methoxythiophen-2-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-trifluoromethylthiophen-2-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(furan-2-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(5-methylfuran-2-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(5-chlorofuran-2-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(5-methoxyfuran-2-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(5-trifluoromethylfuran-2-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-methylfuran-2-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-chlorofuran-2-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-methoxyfuran-2-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-trifluoromethylfuran-2-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(oxazol-2-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(oxazol-S-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(thiazol-2-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(thiazol-5-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-([1,3,4]oxadiazol-2-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-([1,3,4]thiadiazol-2-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-aminophenylsulfanyl)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(3-aminophenylsulfanyl)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(2-aminophenylsulfanyl)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-acetylphenylsulfanyl)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(3-acetylphenylsulfanyl)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(2-acetylphenylsulfanyl)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-carbamoylphenylsulfanyl)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(3-carbamoylphenylsulfanyl)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(2-carbamoylphenylsulfanyl)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-hydroxyphenylsulfanyl)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(3-hydroxyphenylsulfanyl)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(2-hydroxyphenylsulfanyl)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-acetamidophenylsulfanyl)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(3-acetamidophenylsulfanyl)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(2-acetamidophenylsulfanyl)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(thiophen-2-ylsulfanyl)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(5-methylthiophen-2-ylsulfanyl)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(5-chlorothiophen-2-ylsulfanyl)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(5-trifluoromethylthiophen-2-ylsulfanyl)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(furan-2-ylsulfanyl)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(5-methylfuran-2-ylsulfanyl)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(5-chlorofuran-2-ylsulfanyl)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(oxazol-2-ylsulfanyl)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1    l]oct-3-yl]-4-(5-chlorooxazol-2-ylsulfanyl)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(5-methoxyoxazol-2-ylsulfanyl)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(5-trifluoromethyloxazol-2-ylsulfanyl)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(oxazol-2-ylsulfanyl)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(oxazol-5-ylsulfanyl)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(thiazol-2-ylsulfanyl)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(thiazol-5-ylsulfanyl)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-([1,3,4]oxadiazol-2-ylsulfanyl)-benzamide;    N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-([1,3,4]thiadiazol-2-ylsulfanyl)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(5-trifluoromethylpyrrol-2-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(3H-imidazol-4-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(isoxazol-2-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(isothiazol-2-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(pyrrol-2-ylsulfanyl)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(3H-imidazol-4-ylsulfanyl)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(isoxazol-2-ylsulfanyl)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(isothiazol-2-ylsulfanyl)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(6-methylpyridin-3-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(6-chloropyridin-3-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(6-methoxypyridin-3-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(6-trifluoromethylpyridin-3-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(2-chloropyridin-4-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(5-chloropyridin-2-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-chloropyridin-2-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(6-chloropyridin-2-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(5-chloropyridin-3-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(2-chloropyridin-3-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-chloropyridin-3-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(3-chloropyridin-4-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(3-chloropyridin-2-yloxy)-benzamide;-   N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(6-chloropyridin-3-ylsulfanyl)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-hydroxyphenoxy)benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-acetamidophenoxy)benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-phenoxybenzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-benzylbenzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(phenylsulfanyl)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-3-phenoxybenzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-fluorophenoxy)benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(2-fluorophenoxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(3-fluorophenoxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(2-chlorophenoxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(3-chlorophenoxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-chlorophenoxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(2-methoxyphenoxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(3-methoxyphenoxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-methoxyphenoxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(3-chlorophenylsulfanyl)benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-chlorophenyl-sulfanyl)benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(2-chlorophenyl-sulfanyl)benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-methoxyphenyl-sulfanyl)benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(3-methoxyphenyl-sulfanyl)benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(2-methoxyphenyl-sulfanyl)benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-aminophenoxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(3-aminophenoxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(2-aminophenoxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-acetylphenoxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(3-acetylphenoxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(2-acetylphenoxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-carbamoylphenoxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(3-carbamoylphenoxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(2-carbamoylphenoxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-cyanophenoxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(3-cyanophenoxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(2-cyanophenoxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(thiophen-2-yloxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(5-methylthiophen-2-yloxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(5-chlorothiophen-2-yloxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(5-methoxythiophen-2-yloxy)-benzamide;-   N-[-azabicyclo[3.2.2]nonan-3-yl]-4-(5-trifluoromethylthiophen-2-yloxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-methylthiophen-2-yloxy)-benzamide;-   -[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-chlorothiophen-2-yloxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-methoxythiophen-2-yloxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-trifluoromethylthiophen-2-yloxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(furan-2-yloxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(5-methylfuran-2-yloxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(5-chlorofuran-2-yloxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(5-methoxyfuran-2-yloxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(5-trifluoromethylfuran-2-yloxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-methylfuran-2-yloxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-chlorofuran-2-yloxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-methoxyfuran-2-yloxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-trifluoromethylfuran-2-yloxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(oxazol-2-yloxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(oxazol-5-yloxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(thiazol-2-yloxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(thiazol-5-yloxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-([1,3,4]oxadiazol-2-yloxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-([1,3,4]thiadiazol-2-yloxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-aminophenylsulfanyl)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(3-aminophenylsulfanyl)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(2-aminophenylsulfanyl)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-acetylphenylsulfanyl)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(3-acetylphenylsulfanyl)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(2-acetylphenylsulfanyl)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-carbamoylphenylsulfanyl)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(3-carbamoylphenylsulfanyl)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(2-carbamoylphenylsulfanyl)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-hydroxyphenylsulfanyl)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(3-hydroxyphenylsulfanyl)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(2-hydroxyphenylsulfanyl)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-acetamidophenylsulfanyl)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(3-acetamidophenylsulfanyl)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(2-acetamidophenylsulfanyl)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(thiophen-2-ylsulfanyl)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(5-methylthiophen-2-ylsulfanyl)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(5-chlorothiophen-2-ylsulfanyl)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(5-trifluoromethylthiophen-2-ylsulfanyl)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(furan-2-ylsulfanyl)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(5-methylfuran-2-ylsulfanyl)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(5-chlorofuran-2-ylsulfanyl)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(oxazol-2-ylsulfanyl)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(5-chlorooxazol-2-ylsulfanyl)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(5-methoxyoxazol-2-ylsulfanyl)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(5-trifluoromethyloxazol-2-ylsulfanyl)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(oxazol-2-ylsulfanyl)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(oxazol-5-ylsulfanyl)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(thiazol-2-ylsulfanyl)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(thiazol-5-ylsulfanyl)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-([1,3,4]oxadiazol-2-ylsulfanyl)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-([1,3,4]thiadiazol-2-ylsulfanyl)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(5-trifluoromethylpyrrol-2-yloxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(3H-imidazol-4-yloxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(isoxazol-2-yloxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(isothiazol-2-yloxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(pyrrol-2-ylsulfanyl)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(3H-imidazol-4-ylsulfanyl)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(isoxazol-2-ylsulfanyl)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(isothiazol-2-ylsulfanyl)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(6-methylpyridin-3-yloxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(6-chloropyridin-3-yloxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(6-methoxypyridin-3-yloxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(6-trifluoromethylpyridin-3-yloxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(2-chloropyridin-4-yloxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(5-chloropyridin-2-yloxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-chloropyridin-2-yloxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(6-chloropyridin-2-yloxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(5-chloropyridin-3-yloxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(2-chloropyridin-3-yloxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-chloropyridin-3-yloxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(3-chloropyridin-4-yloxy)-benzamide;-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(3-chloropyridin-2-yloxy)-benzamide;    or-   N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(6-chloropyridin-3-ylsulfanyl)-benzamide.

The present invention also includes, by representation but notlimitation, any one or more or combination of the following compoundsand pharmaceutically acceptable salts thereof, both of which can be madeby one of ordinary skill in the art using the procedures provided makingnon-critical changes:

-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(4-hydroxyphenoxy)benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(4-acetamidophenoxy)benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-phenoxybenzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-benzylbenzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(phenylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-3-phenoxybenzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(4-fluorophenoxy)benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(2-fluorophenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(3-fluorophenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(2-chlorophenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(3-chlorophenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(4-chlorophenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(2-methoxyphenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(3-methoxyphenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(4-methoxyphenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(3-chlorophenylsulfanyl)benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(4-chlorophenyl-sulfanyl)benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(2-chlorophenyl-sulfanyl)benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(4-methoxyphenyl-sulfanyl)benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(3-methoxyphenyl-sulfanyl)benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(2-methoxyphenyl-sulfanyl)benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(4-aminophenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(3-aminophenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(2-aminophenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(4-acetylphenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(3-acetylphenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(2-acetylphenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(4-carbamoylphenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(3-carbamoylphenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(2-carbamoylphenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(4-cyanophenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(3-cyanophenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(2-cyanophenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(thiophen-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(5-methylthiophen-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(5-chlorothiophen-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(5-methoxythiophen-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(5-trifluoromethylthiophen-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(4-methylthiophen-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(4-chlorothiophen-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(4-methoxythiophen-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(4-trifluoromethylthiophen-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(furan-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(5-methylfuran-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(5-chlorofuran-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(5-methoxyfuran-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(5-trifluoromethylfuran-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(4-methylfuran-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(4-chlorofuran-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(4-methoxyfuran-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(4-trifluoromethylfuran-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(oxazol-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(oxazol-5-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(thiazol-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(thiazol-5-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-([1,3,4]oxadiazol-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-([1,3,4]thiadiazol-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(4-aminophenylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(3-aminophenylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(2-aminophenylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(4-acetylphenylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(3-acetylphenylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(2-acetylphenylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(4-carbamoylphenylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(3-carbamoylphenylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(2-carbamoylphenylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(4-hydroxyphenylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(3-hydroxyphenylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(2-hydroxyphenylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(4-acetamidophenylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(3-acetamidophenylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(2-acetamidophenylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(thiophen-2-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(5-methylthiophen-2-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(5-chlorothiophen-2-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(5-trifluoromethylthiophen-2-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(furan-2-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(5-methylfuran-2-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(5-chlorofuran-2-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(oxazol-2-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(5-chlorooxazol-2-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(5-methoxyoxazol-2-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(5-trifluoromethyloxazol-2-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(oxazol-2-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(oxazol-5-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(thiazol-2-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(thiazol-5-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-([1,3,4]oxadiazol-2-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-([1,3,4]thiadiazol-2-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(5-trifluoromethylpyrrol-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(3H-imidazol-4-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(isoxazol-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(isothiazol-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(pyrrol-2-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(3H-imidazol-4-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(isoxazol-2-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(isothiazol-2-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(6-methylpyridin-3-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(6-chloropyridin-3-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(6-methoxypyridin-3-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(6-trifluoromethylpyridin-3-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(2-chloropyridin-4-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(5-chloropyridin-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(4-chloropyridin-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(6-chloropyridin-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(5-chloropyridin-3-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(2-chloropyridin-3-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(4-chloropyridin-3-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(3-chloropyridin-4-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(3-chloropyridin-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-5-yl]-4-(6-chloropyridin-3-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(4-hydroxyphenoxy)benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(4-acetamidophenoxy)benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-phenoxybenzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-benzylbenzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(phenylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-3-phenoxybenzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(4-fluorophenoxy)benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(2-fluorophenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(3-fluorophenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(2-chlorophenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(3-chlorophenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(4-chlorophenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(2-methoxyphenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(3-methoxyphenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(4-methoxyphenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(3-chlorophenylsulfanyl)benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(4-chlorophenyl-sulfanyl)benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(2-chlorophenyl-sulfanyl)benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(4-methoxyphenyl-sulfanyl)benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(3-methoxyphenyl-sulfanyl)benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(2-methoxyphenyl-sulfanyl)benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(4-aminophenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(3-aminophenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(2-aminophenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(4-acetylphenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(3-acetylphenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(2-acetylphenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(4-carbamoylphenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(3-carbamoylphenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(2-carbamoylphenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(4-cyanophenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(3-cyanophenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(2-cyanophenoxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(thiophen-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(5-methylthiophen-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(5-chlorothiophen-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(5-methoxythiophen-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(5-trifluoromethylthiophen-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(4-methylthiophen-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(4-chlorothiophen-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(4-methoxythiophen-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(4-trifluoromethylthiophen-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(furan-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(5-methylfuran-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(5-chlorofuran-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(5-methoxyfuran-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(5-trifluoromethylfuran-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(4-methylfuran-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(4-chlorofuran-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(4-methoxyfuran-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(4-trifluoromethylfuran-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(oxazol-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(oxazol-5-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(thiazol-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(thiazol-5-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-([1,3,4]oxadiazol-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-([1,3,4]thiadiazol-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(4-aminophenylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(3-aminophenylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(2-aminophenylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(4-acetylphenylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(3-acetylphenylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(2-acetylphenylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(4-carbamoylphenylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(3-carbamoylphenylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(2-carbamoylphenylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(4-hydroxyphenylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(3-hydroxyphenylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(2-hydroxyphenylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(4-acetamidophenylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(3-acetamidophenylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(2-acetamidophenylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(thiophen-2-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(5-methylthiophen-2-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(5-chlorothiophen-2-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(5-trifluoromethylthiophen-2-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(furan-2-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(5-methylfuran-2-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(5-chlorofuran-2-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(oxazol-2-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(5-chlorooxazol-2-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(5-methoxyoxazol-2-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(5-trifluoromethyloxazol-2-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(oxazol-2-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(oxazol-5-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(thiazol-2-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(thiazol-5-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-([1,3,4]oxadiazol-2-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-([1,3,4]thiadiazol-2-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(5-trifluoromethylpyrrol-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(3H-imidazol-4-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(isoxazol-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(isothiazol-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(pyrrol-2-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(3H-imidazol-4-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(isoxazol-2-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(isothiazol-2-ylsulfanyl)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(6-methylpyridin-3-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(6-chloropyridin-3-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(6-methoxypyridin-3-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(6-trifluoromethylpyridin-3-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(2-chloropyridin-4-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(5-chloropyridin-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(4-chloropyridin-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(6-chloropyridin-2-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(5-chloropyridin-3-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(2-chloropyridin-3-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(4-chloropyridin-3-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(3-chloropyridin-4-yloxy)-benzamide;-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(3-chloropyridin-2-yloxy)-benzamide;    or-   N-[2-azabicyclo[2.2.1]hept-6-yl]-4-(6-chloropyridin-3-ylsulfanyl)-benzamide,    any of which is optionally substituted on the Azabicyclo moiety with    lower alkyl for R₂, including methyl, as discussed herein, provided    that the Azabicyclo moiety has only one substituent for R₂.

Materials and Methods for Determining α7 nAChR Agonist Activity

Cell-based Assay for Measuring the EC₅₀ of α7 nAChR Agonists

Construction and Expression of the α7-5HT₃ Receptor

The cDNA encoding the N-terminal 201 amino acids from the human α7 nAChRthat contain the ligand binding domain of the ion channel was fused tothe cDNA encoding the pore forming region of the mouse 5HT₃ receptor asdescribed by Eisele J L, et al., Chimaeric nicotinic-serotonergicreceptor combines distinct ligand binding and channel specificities,Nature (1993), Dec. 2;366(6454):479-83, and modified by Groppi, et al.,WO 00/73431. The chimeric α7-5HT₃ ion channel was inserted into pGS175and pGS179 which contain the resistance genes for G-418 and hyrgromycinB, respectively. Both plasmids were simultaneously transfected intoSH-EP1 cells and cell lines were selected that were resistant to bothG-418 and hyrgromycin B. Cell lines expressing the chimeric ion channelwere identified by their ability to bind fluorescent α-bungarotoxin ontheir cell surface. The cells with the highest amount of fluorescentα-bungarotoxin binding were isolated using a Fluorescent Activated CellSorter (FACS). Cell lines that stably expressed the chimeric α7-5HT₃were identified by measuring fluorescent α-bungarotoxin binding aftergrowing the cells in minimal essential medium containing nonessentialamino acids supplemented with 10% fetal bovine serum, L-glutamine, 100units/ml penicillin/streptomycin, 250 ng/mg fungizone, 400 μg/mlhygromycin B, and 400 μg/ml G-418 at 370° C. with 6% CO₂ in a standardmammalian cell incubator for at least 4 weeks in continuous culture.

Assay of the Activity of the Chimeric α7-5HT₃ Receptor

To assay the activity of the α7-5HT₃ ion channel, cells expressing thechannel were plated into each well of either a 96 or 384 well dish(Coming #3614) and grown to confluence prior to assay. On the day of theassay, the cells were loaded with a 1:1 mixture of 2 mM Calcium Green 1,AM (Molecular Probes) dissolved in anhydrous DMSO and 20% pluronic F-127(Molecular Probes). This solution was added directly to the growth mediaof each well to achieve a final concentration 2 μM. The cells wereincubated with the dye for 60 min at 370° C. and then washed with amodified version of Earle's balanced salt solution (MMEBSS) as describedin WO 00/73431. The ion conditions of the MMEBSS was adjusted tomaximize the flux of calcium ion through the chimeric α7-5HT₃ ionchannel as described in WO 00/73431. The activity of compounds on thechimeric α7-5HT₃ ion channel was analyzed on FLIPR. The instrument wasset up with an excitation wavelength of 488 nanometers using 500milliwatts of power. Fluorescent emission was measured above 525nanometers with an appropriate F-stop to maintain a maximal signal tonoise ratio. Agonist activity of each compound was measured by directlyadding the compound to cells expressing the chimeric α7-5HT₃ ion channeland measuring the resulting increase in intracellular calcium that iscaused by the agonist-induced activation of the chimeric ion channel.The assay is quantitative such that concentration-dependent increase inintracelluar calcium is measured as concentration-dependent change inCalcium Green fluorescence. The effective concentration needed for acompound to cause a 50% maximal increase in intracellular calcium istermed the EC₅₀. The most active compounds would have EC₅₀ values fromabout 0.01 μM to about 50 μM.

Binding Constants

Another way for measuring α7 nAChR agonist activity is to determinebinding constants of a potential agonist in a competition binding assay.For α7 nAChR agonists, there is good correlation between functional EC₅₀values using the chimeric α7-5HT₃ ion channel as a drug target andbinding affinity of compounds to the endogenous α7 nAChR.

Membrane Preparation

Male Sprague-Dawley rats (300-350 g) are sacrificed by decapitation andthe brains (whole brain minus cerebellum) are dissected quickly, weighedand homogenized in 9 volumes/g wet weight of ice-cold 0.32 M sucroseusing a rotating pestle on setting 50 (10 up and down strokes). Thehomogenate is centrifuged at 1,000×g for 10 minutes at 4° C. Thesupernatant is collected and centrifuged at 20,000×g for 20 minutes at4° C. The resulting pellet is resuspended to a protein concentration of1-8 mg/mL. Aliquots of 5 mL homogenate are frozen at −80° C. untilneeded for the assay. On the day of the assay, aliquots are thawed at rtand diluted with Kreb's −20 mM Hepes buffer pH 7.0 (at rt) containing4.16 mM NaHCO₃, 0.44 mM KH₂PO₄, 127 mM NaCl, 5.36 mM KCl, 1.26 mM CaCl₂,and 0.98 mM MgCl₂, so that 25-150 μg protein are added per test tube.Proteins are determined by the Bradford method (Bradford, M. M., Anal.Biochem., 72, 248-254, 1976) using bovine serum albumin as the standard.

Binding Assay

For saturation studies, 0.4 mL homogenate are added to test tubescontaining buffer and various concentrations of radioligand, and areincubated in a final volume of 0.5 mL for 1 hour at 25° C. Nonspecificbinding was determined in tissues incubated in parallel in the presenceof 0.05 mls MLA for a final concentration of 1 μM, added before theradioligand. In competition studies, drugs are added in increasingconcentrations to the test tubes before addition of 0.05 mls [³H]-MLAfor a final concentration 3.0 to 4.0 nM. The incubations are terminatedby rapid vacuum filtration through Whatman GF/B glass filter papermounted on a 48 well Brandel cell harvester. Filters are pre-soaked in50 mM Tris HCl pH 7.0-0.05% polyethylenimine. The filters are rapidlywashed two times with 5 mL aliquots of cold 0.9% saline and then countedfor radioactivity by liquid scintillation spectrometry.

Data Analysis

In competition binding studies, the inhibition constant (Ki) wascalculated from the concentration dependent inhibition of [³H]-MLAbinding obtained from non-linear regression fitting program according tothe Cheng-Prusoff equation (Cheng, Y. C. and Prussoff, W. H., Biochem.Pharmacol., 22, p. 3099-3108, 1973). Hill coefficients were obtainedusing non-linear regression (GraphPad Prism sigmoidal dose-response withvariable slope).

1. A compound of the Formula I:

wherein X is O or S; Azabicyclo is:

R₁ is independently H, alkyl, cycloalkyl, halogenated alkyl, and aryl; R₂ is F, Cl, Br, I, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, or aryl, provided that when Azabicyclo is I, R₂ is alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, or aryl, and further provided that R₂ is absent when any of k₂, k₅, or k₆ is 0; k₂ is 0 or 1; k₅ is 0, 1, or 2; k₆ is 0, 1, or 2; R₃ is H, F, Cl, Br, I, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, halogenated cycloalkyl, halogenated heterocycloalkyl, aryl, R₇, R₉, —OR₈, —SR₈, —S(O)₂R₈, —S(O)R₈, —OS(O)₂R₈, —N(R₈)₂, —C(O)R₈, —C(S)R₈, —C(O)OR₈, —CN, —C(O)N(R₈)₂, —NR₈C(O)R₈, —S(O)₂N(R₈)₂, —NR₈S(O)₂R₈, —NO₂, —N(R₈)C(O)N(R₈)₂, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted heterocycloalkyl, phenyl, phenyl having 1-4 substituents independently selected from F, Cl, Br, I and R₂₁, naphthyl, or naphthyl having 1-4 substituents independently selected from F, Cl, Br, I, R₂₁; R₄ is —O—R₅, —S—R₅, —S(O)—R₅, —C(O)—R₅, or alkyl substituted on the ω carbon with R₅ where said ω carbon is determined by counting the longest carbon chain of the alkyl moiety with the C-1 carbon being the carbon attached to the phenyl ring of the core molecule and the ω carbon being the carbon furthest from said C-1 carbon; R₅ is aryl, R₇, or R₉; R₇ is 5-membered heteroaromatic mono-cyclic moieties containing within the ring 1-3 heteroatoms independently selected from —O—, —N—, —N(R₁₄)—, and —S—, and having 0-1 substituent selected from R₁₂ and 0-3 substituents independently selected from F, Cl, Br, or I, or R₇ is a 9-membered fused-ring moiety having a 6-membered ring fused to a 5-membered ring and having the formula:

wherein each A is independently CR₁₈ or N, provided that only up to one A is N, E<1> and E<2> are independently selected from CR₁₈, O, S, or NR₁₄, and G is CR₁₈, provided that R₁₈ or R₁₄ of E<1>, E<2>, and G can be a bond when - - - forms a double bond and further provided that R₁₈ or R₁₄ can be a bond for bonding R₇ to a moiety to which it is attached; Each R₈ is independently H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl, substituted heterocycloalkyl, R₇, R₉, phenyl, or substituted phenyl; R₉ is 6-membered heteroaromatic mono-cyclic moieties containing within the ring 1-3 heteroatoms selected from —N— and having 0-1 substituent selected from R₁₂ and 0-3 substituent(s) independently selected from F, Cl, Br, or I, or R₉ is 10-membered heteroaromatic bi-cyclic moieties containing within one or both rings 1-3 heteroatoms selected from ═N—, each 10-membered fused-ring moiety having 0-1 substituent selected from R₁₂ and 0-3 substituent(s) independently selected from F, Cl, Br, or I and having a bond for bonding R₉ to a moiety to which it is attached where valency allows; Each R₁₁ is independently H, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, or halogenated heterocycloalkyl; R₁₂ is —OR₁₁, —SR₁₁, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, —NR₁₁R₁₁, —C(O)R₁, —NO₂, —C(O)NR₁₁R₁₁, —CN, —NR₁₁C(O)R₁, —S(O)₂NR₁₁R₁₁, or —NR₁₁S(O)₂R, ₁; R₁₃ is —OR₁, —SR₁₁, —NR₁₁R₁₁, —C(O)R₁₁, —C(O)NR₁₁R₁₁, —CN, —CF₃, to —NR₁₁C(O)R₁, —S(O)₂NR₁₁R₁₁, —NR₁₁S(O)₂R₁₁, or —NO₂; R₁₄ is a bond, H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl, substituted heterocycloalkyl, phenyl, phenyl having 1 substituent selected from R₂₀ and further having 0-3 substituents independently selected from F, Cl, Br, or I; Each R₁₈ is independently H, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, —OR₁₁, —SR₁₁, —N(R, ₁)₂, —C(O)R₁, —NO₂, —C(O)N(R₁₁)₂, —CN, —NR₁₁C(O)R₁, —S(O)₂N(R₁₁)₂, or —NR₁₁S(O)₂R₁, F, Cl, Br, or I, or a bond; R₂₀ is alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, —OR₁₁, —SR₁₁, —N(R₁₁)₂, —C(O)R₁, —C(O)N(R₁₁)₂, —CN, —NR₁₁C(O)R₁₁, —S(O)₂N(R₁₁)₂, —NR₁₁S(O)₂R₁₁, —NO₂, alkyl substituted with 1-4 substituent(s) independently selected from F, Cl, Br, I, or R₁₃, cycloalkyl substituted with 1-4 substituent(s) independently selected from F, Cl, Br, I, or R₁₃, or heterocycloalkyl substituted with 1-4 substituent(s) independently selected from F, Cl, Br, I, or R₁₃; Each R₂₁ is independently alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl, substituted heterocycloalkyl, R₇, R₉, phenyl, or phenyl having 1 substituent selected from R₂₀ and further having 0-3 substituents independently selected from F, Cl, Br, or I; or pharmaceutically acceptable salt thereof.
 2. The compound of claim 1, wherein X is O.
 3. The compound of claim 2, wherein R₁ is H, lower alkyl, or lower cycloalkyl, wherein R₂ is lower alkyl, lower halogenated alkyl, or lower substituted alkyl, provided that R₂ is present, or R₂ is absent, and wherein k₂, k₅, or k₆ is 0, or
 1. 4. The compound of claim 3, wherein R₃ is H, F, Cl, Br, I, lower alkyl, lower halogenated alkyl, —OR₈, —N(R₈)₂, —C(O)NH(R₈), —NR₈C(O)R₈.
 5. The compound of claim 4, wherein R₁ is H.
 6. The compound of claim 5, wherein Azabicyclo is II, V, or VI.
 7. The compound of claim 6, wherein each k₂, k₅, or k₆ is
 0. 8. The compound of claim 7, wherein the compound is exo-N-[(4S)-1-azabicyclo[2.2.11]hept-3-yl]-4-(4-acetamidophenoxy)benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-acetamidophenoxy)benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-phenoxybenzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-benzylbenzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(phenylsulfanyl)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-phenoxybenzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-fluorophenoxy)benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(2-fluorophenoxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3-fluorophenoxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(2-chlorophenoxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3-chlorophenoxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-chlorophenoxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(2-methoxyphenoxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3-methoxyphenoxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-methoxyphenoxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3-chlorophenylsulfanyl)benza-mide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-chlorophenyl-sulfanyl)benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(2-chlorophenyl-sulfanyl)benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-methoxyphenyl-sulfanyl)benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3-methoxyphenyl-sulfanyl)benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(2-methoxyphenyl-sulfanyl)benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-aminophenoxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3-aminophenoxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(2-aminophenoxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-acetylphenoxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3-acetylphenoxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(2-acetylphenoxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-carbamoylphenoxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3-carbamoylphenoxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(2-carbamoylphenoxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-cyanophenoxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3-cyanophenoxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(2-cyanophenoxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(thiophen-2-yloxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(5-methylthiophen-2-yloxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(5-chlorothiophen-2-yloxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(5-methoxythiophen-2-yloxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(5-trifluoromethylthiophen-2-yloxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-methylthiophen-2-yloxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-chlorothiophen-2-yloxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl-]-4-(4-methoxythiophen-2-yloxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-trifluoromethylthiophen-2-yloxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(furan-2-yloxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(5-methylfuran-2-yloxy)-benza-mide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(5-chlorofuran-2-yloxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(5-methoxyfuran-2-yloxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(5-trifluoromethylfuran-2-yloxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-methylfuran-2-yloxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-chlorofuran-2-yloxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-methoxyfuran-2-yloxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-trifluoromethylfuran-2-yloxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(oxazol-2-yloxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(oxazol-5-yloxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(thiazol-2-yloxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(thiazol-5-yloxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-([1,3,4]oxadiazol-2-yloxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-([1,3,4]thiadiazol-2-yloxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl-4-(4-aminophenylsulfanyl)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3-aminophenylsulfanyl)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(2-aminophenylsulfanyl)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-acetylphenylsulfanyl)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3-acetylphenylsulfanyl)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(2-acetylphenylsulfanyl)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-carbamoylphenylsulfanyl)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3-carbamoylphenylsulfanyl)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(2-carbamoylphenylsulfanyl)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-hydroxyphenylsulfanyl)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3-hydroxyphenylsulfanyl)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(2-hydroxyphenylsulfanyl)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-acetamidophenylsulfanyl)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3-acetamidophenylsulfanyl)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(2-acetamidophenylsulfanyl)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(thiophen-2-ylsulfanyl)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(5-methylthiophen-2-ylsulfanyl)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(5-chlorothiophen-2-ylsulfanyl)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(5-trifluoromethylthiophen-2-ylsulfanyl)benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(furan-2-ylsulfanyl)-benzamid-e; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(5-methylfuran-2-ylsulfanyl)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(5-chlorofuran-2-ylsulfanyl)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(oxazol-2-ylsulfanyl)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(5-chlorooxazol-2-ylsulfanyl)-benzamide; exo-N4(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(5-methoxyoxazol-2-ylsulfanyl)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(5-trifluoromethyloxazol-2-ylsulfanyl)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(oxazol-2-ylsulfanyl)-benzami-de; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(oxazol-5-ylsulfanyl)-benz-amide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(thiazol-2-ylsulfanyl)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(thiazol-5-ylsulfan-yl)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-([1,3,4]oxadiazol-2-ylsulfanyl)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-([1,3,4]thiadiazol-2-ylsulfanyl)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(5-trifluoromethylpyrrol-2-yloxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3H-imidazol-4-yloxy)-benzami-de; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(isoxazol-2-yloxy)-benzami-de; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(isothiazol-2-yloxy)-benza-mide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(pyrrol-2-ylsulfanyl)-be-nzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3H-imidazol-4-ylsulfanyl)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl-4-(isoxazol-2-ylsulfanyl)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(isothiazol-2-ylsulfanyl)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(6-methylpyridin-3-yloxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(6-chloropyridin-3-yloxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(6-methoxypyridin-3-yloxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(6-trifluoromethylpyridin-3-yloxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(2-chloropyridin-4-yloxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(5-chloropyridin-2-yloxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-chloropyridin-2-yloxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(6-chloropyridin-2-yloxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(5-chloropyridin-3-yloxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(2-chloropyridin-3-yloxy)-benzamide; exo-N-(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(4-chloropyridin-3-yloxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3-chloropyridin-4-yloxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(3-chloropyridin-2-yloxy)-benzamide; exo-N-[(4S)-1-azabicyclo[2.2.1]hept-3-yl]-4-(6-chloropyridin-3-ylsulfanyl)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-hydroxyphenoxy)benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-acetamidophenoxy)benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-phenoxybenzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-benzylbenzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(phenylsulfanyl)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-phenoxybenzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-fluorophenoxy)benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(2-fluorophenoxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(3-fluorophenoxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(2-chlorophenoxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(3-chlorophenoxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-chlorophenoxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(2-methoxyphenoxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(3-methoxyphenoxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-methoxyphenoxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(3-chlorophenylsulfanyl)benzami-de; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-chlorophenyl-sulfanyl)ben-zamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(2-chlorophenyl-sulfanyl-)benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-methoxyphenyl-sul-fanyl)benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(3-methoxypheny-l-sulfanyl)benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(2-methoxy-phenyl-sulfanyl)benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-am-inophenoxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(3-aminop-henoxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(2-aminopheno-xy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-acetylphenoxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(3-acetylphenoxy)-be-nzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(2-acetylphenoxy)-benza-mide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-carbamoylphenoxy)-benza-mide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(3-carbamoylphenoxy)-benza-mide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(2-carbamoylphenoxy)-benza-mide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-cyanophenoxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(3-cyanophenoxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(2-cyanophenoxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(thiophen-2-yloxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(5-methylthiophen-2-yloxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(5-chlorothiophen-2-yloxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(5-methoxythiophen-2-yloxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(5-trifluoromethylthiophen-2-yloxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-methylthiophen-2-yloxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-chlorothiophen-2-yloxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-methoxythiophen-2-yloxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-trifluoromethylthiophen-2-yloxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(furan-2-yloxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(5-methylfuran-2-yloxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(5-chlorofuran-2-yloxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(5-methoxyfuran-2-yloxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(5-trifluoromethylfuran-2-yloxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-methylfuran-2-yloxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-chlorofuran-2-yloxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-methoxyfuran-2-yloxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-trifluoromethylfuran-2-yloxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(oxazol-2-yloxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(oxazol-5-yloxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(thiazol-2-yloxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(thiazol-5-yloxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-([1,3,4]oxadiazol-2-yloxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-([1,3,4]thiadiazol-2-yloxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-aminophenylsulfanyl)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(3-aminophenylsulfanyl)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(2-aminophenylsulfanyl)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-acetylphenylsulfanyl)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(3-acetylphenylsulfanyl)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(2-acetylphenylsulfanyl)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-carbamoylphenylsulfanyl)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(3-carbamoylphenylsulfanyl)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(2-carbamoylphenylsulfanyl)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-hydroxyphenylsulfanyl)-benza-mide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(3-hydroxyphenylsulfanyl)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(2-hydroxyphonylsulfa-nyl)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-acetamidophenylsulfanyl)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(3-acetamidophenylsulfanyl)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(2-acetamidophenylsulfanyl)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(thiophen-2-ylsulfanyl)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(5-methylthiophen-2-ylsulfanyl)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(5-chlorothiophen-2-ylsulfanyl)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(5-trifluoromethylthiophen-2-ylsulfanyl)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(furan-2-ylsulfanyl)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(5-methylfuran-2-ylsulfanyl)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(5-chlorofuran-2-ylsulfanyl)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(oxazol-2-ylsulfanyl)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(5-chlorooxazol-2-ylsulfanyl)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(5-methoxyoxazol-2-ylsulfanyl)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(5-trifluoromethyloxazol-2-ylsulfanyl)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(oxazol-2-ylsulfanyl)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(oxazol-5-ylsulfanyl)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(thiazol-2-ylsulfanyl)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(thiazol-5-ylsulfanyl)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-([1,3,4]oxadiazol-2-ylsulfanyl)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-([1,3,4]thiadiazol-2-ylsulfanyl)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(5-trifluoromethylpyrrol-2-yloxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(3H-imidazol-4-yloxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(isoxazol-2-yloxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(isothiazol-2-yloxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(pyrrol-2-ylsulfanyl)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(3H-imidazol-4-ylsulfanyl)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(isoxazol-2-ylsulfanyl)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(isothiazol-2-ylsulfanyl)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(6-methylpyridin-3-yloxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(6-chloropyridin-3-yloxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(6-methoxypyridin-3-yloxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(6-trifluoromethylpyridin-3-yloxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(2-chloropyridin-4-yloxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(5-chloropyridin-2-yloxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-chloropyridin-2-yloxy)-benza-mide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(6-chloropyridin-2-yloxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(5-chloropyridin-3-yl-oxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(2-chloropyridin-3-yloxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(4-chloropy-ridin-3-yloxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(3-chl-oropyridin-4-yloxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(-3-chloropyridin-2-yloxy)-benzamide; N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-4-(6-chloropyridin-3-ylsulfanyl)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-hydroxyphenoxy)benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-acetamidophenoxy)benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-phenoxybenzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-benzylbenzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(phenylsulfanyl)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-3-phenoxybenzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-fluorophenoxy)benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(2-fluorophenoxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(3-fluorophenoxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(2-chlorophenoxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(3-chlorophenoxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-chlorophenoxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(2-methoxyphenoxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(3-methoxyphenoxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-methoxyphenoxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(3-chlorophenylsulfanyl)benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-chlorophenyl-sulfanyl)benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(2-chlorophenyl-sulfanyl)benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-methoxyphenyl-sulfanyl)benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(3-methoxyphenyl-sulfanyl)benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(2-methoxyphenyl-sulfanyl)benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-aminophenoxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(3-aminophenoxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(2-aminophenoxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-acetylphenoxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(3-acetylphenoxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(2-acetylphenoxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-carbamoylphenoxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(3-carbamoylphenoxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(2-carbamoylphenoxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-cyanophenoxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(3-cyanophenoxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(2-cyanophenoxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(thiophen-2-yloxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(5-methylthiophen-2-yloxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(5-chlorothiophen-2-yloxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(5-methoxythiophen-2-yloxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(5-trifluoromethylthiophen-2-yloxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-methylthiophen-2-yloxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-chlorothiophen-2-yloxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-methoxythiophen-2-yloxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-trifluoromethylthiophen-2-yloxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(furan-2-yloxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(5-methylfuran-2-yloxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(5-chlorofuran-2-yloxy)-benzami-de; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(5-methoxyfuran-2-yloxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(5-trifluoromethylfuran-2-yloxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-methylfuran-2-yloxy)-benzam-ide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-chlorofuran-2-yloxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-methoxyfuran-2-yloxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-trifluoromethylfuran-2-yloxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(oxazol-2-yloxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(oxazol-5-yloxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(thiazol-2-yloxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(thiazol-5-yloxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-([1,3,4]oxadiazol-2-yloxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-([1,3,4]thiadiazol-2-yloxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-aminophenylsulfanyl)-benzamide; N-[11-azabicyclo[3.2.2]nonan-3-yl]-4-(3-aminophenylsulfanyl)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(2-aminophenylsulfanyl)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-acetylphenylsulfanyl)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(3-acetylphenylsulfanyl)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(2-acetylphenylsulfanyl)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-carbamoylphenylsulfanyl)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(3-carbamoylphenylsulfanyl)-benzamid-e; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(2-carbamoylphenylsulfanyl)-benzami-de; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-hydroxyphenylsulfanyl)-benzamid-e; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(3-hydroxyphenylsulfanyl)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(2-hydroxyphenylsulfanyl)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-acetamidophenylsulfanyl)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(3-acetamidophenylsulfanyl)-benzamid-e; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(2-acetamidophenylsulfanyl)-benzami-de; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(thiophen-2-ylsulfanyl)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(5-methylthiophen-2-ylsulfanyl)-benza-mide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(5-chloro thiophen-2-ylsulfanyl)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(5-trifluoromethylthiophen-2-ylsulfanyl)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(furan-2-ylsulfanyl)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(5-methylfuran-2-ylsulfanyl)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(5-chlorofuran-2-ylsulfanyl)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(oxazol-2-ylsulfanyl)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(5-chlorooxazol-2-ylsulfanyl)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(5-methoxyoxazol-2-ylsulfanyl)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(5-trifluoromethyloxazol-2-ylsulfanyl)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(oxazol-2-ylsulfanyl)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(oxazol-5-ylsulfanyl)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(thiazol-2-ylsulfanyl)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(thiazol-5-ylsulfanyl)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-([1,3,4]oxadiazol-2-ylsulfanyl)-benza-mide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-([1,3,4]thiadiazol-2-ylsulfanyl)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(5-trifluoromethylpyrrol-2-yloxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(3H-imidazol-4-yloxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(isoxazol-2-yloxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(isothiazol-2-yloxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(pyrrol-2-ylsulfanyl)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-y]-4-(3H-imidazol-4-ylsulfanyl)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(isoxazol-2-ylsulfanyl)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(isothiazol-2-ylsulfanyl)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(6-methylpyridin-3-yloxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(6-chloropyridin-3-yloxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(6-methoxypyridin-3-yloxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(6-trifluoromethylpyridin-3-yloxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(2-chloropyridin-4-yloxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(5-chloropyridin-2-yloxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-chloropyridin-2-yloxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(6-chloropyridin-2-yloxy)-benzam-ide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(5-chloropyridin-3-yloxy)-benzami-de; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(2-chloropyridin-3-yloxy)-benzamid-e; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(4-chloropyridin-3-yloxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(3-chloropyridin-4-yloxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(3-chloropyridin-2-yloxy)-benzamide; N-[1-azabicyclo[3.2.2]nonan-3-yl]-4-(6-chloropyridin-3-ylsulfanyl)-benzamide; or pharmaceutically acceptable salt thereof.
 9. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.
 10. The pharmaceutical composition according to claim 9, wherein said compound is administered rectally, topically, orally, sublingually, or parenterally for a therapeutically effective interval.
 11. The pharmaceutical composition according to claim 10, wherein said compound is administered in an amount of from about 0.001 to about 100 mg/kg of body weight of said mammal per day.
 12. The pharmaceutical composition according to claim 10, wherein said compound is administered in an amount of from about 0.1 to about 50 mg/kg of body weight of said mammal per day. 